Individual stereosiomers of 7-[3-(aminoalkyl)-1-pyrrolidinyl]-quinolones and naphthyridones as antibacterial agents

ABSTRACT

Individual stereoisomers of 7-[3-(1-aminoalkyl)-1-pyrrolidinyl]-quinolones and naphthyridones are described, their therapeutic advantages as antibacterial agents, as well as a novel method for the preparation and isolation of such stereoisomers.

This is a divisional of U.S. application Ser. No. 08/221,146 filed Mar.30, 1994, now U.S. Pat. No. 5,461,165 which is a divisional of U.S.application Ser. No. 08/084,044 filed Jun. 28, 1993, now U.S. Pat. No.5,344,940, which is a divisional of U.S. application Ser. No. 07/966,651filed Oct. 26, 1992, now U.S. Pat. No. 5,258,528, which is a divisionalof U.S. application Ser. No. 07/731,825 filed Jul. 15, 1991, nowabandoned, which is a continuation-in-part of U.S. application Ser. No.07/621,201 filed Nov. 30, 1990, now abandoned.

BACKGROUND OF THE INVENTION

The identification and selection of an antibacterial chemotherapeuticagent for development depends on several properties. These include invitro potency against bacteria, in vivo efficacy in animals and man,pharmacokinetic parameters such as good plasma levels and favorablemetabolism, and reduced side effects and toxicity. The ideal agentshould have the best blend of these properties.

Within the quinolone/naphthyridone class of antibacterials efforts aredirected toward increasing in vitro and in vivo efficacy while loweringcertain side effects such as phototoxicity and cytotoxicity and reducinggeneral toxicity as well.

It is also known that within the chiral environment of living organisms,individual stereoisomers/enantiomers of drugs may show unique propertiesrelative to the racemic mixtures. When this occurs, the optimalproperties of the drug can only be obtained when the most favorablestereoisomer is utilized in its pure chiral form.

U.S. Pat. No. 4,665,079 shows quinolones and naphthyridones bystructural formula to have 7-[3-(1-aminoalkyl)-1-pyrrolidinyl]sidechains. These compounds of formula A, where R₁ or R₂ ##STR1## are alkylor hydrogen were revealed to have good antibacterial in vitro potency.European Patent Publication 207,420 describes such compounds having thetwo asymmetric centers in the C₇ side chain of thequinolone/naphthyridone and the preparation of two diastereomericmixtures, each containing two nonseparable enantiomers of formula B andC. ##STR2##

The mixtures B and C were described to possess improved in vivo activityrelative to unsubstituted compounds (Formula A, where R₁ and R₂ arehydrogen). All data reported were for the mixtures, and no method ofseparation of the mixtures was described. At the International Congressof Antimicrobial Agents and Chemotherapy (ICAAC) in Houston, Tex., 1989,there were reported certain individual enantiomers of 1-ethyl and1-cyclopropyl-6,8-difluoro-quinolone-3-carboxylic acids. The3-(R)-1'-(S) stereoisomers were disclosed to have the most potentactivity in vitro. One stereoisomer (3R,1'S) was shown to have improvedin vivo efficacy relative to an unsubstituted analog. Except for the invitro data, no other comparisons among the pure stereoisemers wereprovided. The method employed to prepare and isolate the individualenantiomers involved putting a chiral auxiliary, N-tosylproline, on theamine side chain and performing a separation, removing theN-tosylproline, then replacing it with a conventional protecting group.

It has now been found that overall therapeutic value, i.e. efficacy andsafety, of individual enantiomers of various7-[3-(1-aminoalkyl)-1-pyrrolidinyl]quinolones and naphthyridones cannotbe predicted until all of the enantiomers are made, separated, andtested.

It has also been found, further, that the use of a chiral auxiliary,such as (S)- or (R)-α-methylbenzylamine, as a protecting group, permitsseparation of diastereomeric amines, thus saving two costly steps in theoverall synthesis of all four stereoisomers of7-[3-(1-aminoalkyl)-1-pyrrolidinyl]quinolones and naphthyridines.

SUMMARY OF THE INVENTION

Accordingly, the present invention includes all four novel enantiomersof the formula I ##STR3## wherein * denotes an asymmetric carbon atom;

X is C--H, C--F, C--Cl, C--OR, C--CF₃ or N;

R₁ is ethyl, cyclopropyl, or 2,4-difluorophenyl;

R₂ is hydrogen, alkyl of 1-4 carbon atoms or a cation;

R₃ is hydrogen, amino, or methyl;

R and R' are each independently hydrogen or alkyl of 1-3 carbon atoms,or a pharmaceutically acceptable acid addition salt thereof; with theproviso that when X is C--F, R₃ is amino or R¹ is 2,4-difluorophenyl.

The invention also includes a pharmaceutical composition which comprisesan antibacterially effective amount of a compound having structuralformula I and the pharmaceutically acceptable salts thereof incombination with a pharmaceutically acceptable carrier.

The invention further includes a method for treating bacterialinfections in a mammal which comprises administering an antibacteriallyeffective amount of the above defined pharmaceutical composition to amammal in need thereof.

The invention in another aspect includes a process for the preparationof a compound of formula I which comprises reacting a compound of theformula II ##STR4## wherein L is fluorine or chlorine or other leavinggroups with an individual stereoisomer of the amine of formula III##STR5## wherein * denotes an asymmetric carbon atom;

R is hydrogen or alkyl of 1-3 carbon atoms; and

R" is hydrogen, alkyl of 1-3 carbon atoms or an amino protecting groupwhich can be removed, if necessary, according to known methods.

The invention in still another aspect includes novel stereoisomers asintermediates which are:

(a) stereoisomers of the formula III ##STR6## wherein * denotesasymmetric carbon atoms;

R and R" are independently hydrogen or alkyl of 1-3 carbon atoms or anamino protecting group which can be removed by known methods;

(b) stereoisomers of the formula IV ##STR7## wherein * and *' denoteasymmetric carbon atoms;

R is hydrogen or alkyl of 1-3 carbon atoms; and

R" is hydrogen, alkyl of 1-3 carbon atoms, acetyl, trifluoroacetyl ort-butyloxycarbonyl;

(c) stereoisomers of the formula V ##STR8## wherein * and *' denoteasymmetric carbon atoms.

Finally, the invention includes a process for the preparation of theindividual enantiomers of the formula III ##STR9## wherein * denotesasymmetric carbon atoms and R and R" are independently hydrogen or alkylof 1-3 carbon atoms which comprises:

(a) converting a chirally fixed pyrrolidin-5-one-3-carboxylic acid ofthe formula VI ##STR10## wherein * and *' is either R or S by knownmethods to a diastereomeric pair of oximes of the formula ##STR11##wherein * and *' are asymmetric carbon atoms;

(b) separating the diastereomers by column chromatography;

(c) reducing each diastereomeric oxime by known means to adiastereomeric pair of amines of the formula VIII ##STR12## (d)separating each of these diastereomeric pairs into the individualdiastereomers by column chromatography;

(e) reducing the 5-pyrrolidinone by known methods and protecting thefree amino group with a suitable protecting group (such as BOC, Acetateetc.) by known methods, if desired;

(f) removing the chiral α-methylbenzyl protecting group byhydrogenolysis, thereby liberating the four, separated diastereomers offormulae IIIa-d, and

(g) converting, if desired, by known means the resulting compounds offormula VIII or III where R is hydrogen to those where R isindependently hydrogen or alkyl of 1-3 carbon atoms. The entire overallprocess can be summarized in Scheme A. ##STR13##

DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS

The quinolones and naphthyridones of the present invention have7-[3-(1-aminoalkyl)-1-pyrrolidinyl] as a side chain. This moiety has twoasymmetric centers and thus is capable of existing in fourstereoisomeric forms. These are illustrated as IIIa-d in Scheme A.

Of the four possible stereoisomers of the quinolones and naphthyridonesof the present invention, it has been found that the 3R,1S stereoisomersare generally more potent in vitro, the 3R,1R stereoisomers being secondbest. However, in vivo efficacy shows the 3R,1S as the generallypreferred stereoisomer with the 3S,1R and the 3R,1R alternating forsecond best. Nevertheless, when considering overall safety and efficacy,i.e. taking potential side effects such as phototoxicity andcytotoxicity into account, the 3S,1R stereoisomers can become overallpreferred.

Particularly valuable quinolones and naphthyridones are:

3R,1S-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,

3R,1S-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1S-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1S-5-amino-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1S-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid,

3R,1S-5-amino-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid,

3R,1S-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8-trifluoromethyl-3-quinolinecarboxylicacid,

3R,1S-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid,

3R,1S-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,

3R,1S-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1S-5-amino-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1S-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid,

3R,1S-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-8-ethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

R,1S-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-1,8-naphthyridine-3-carboxylicacid,

R,1S-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

R,1S-5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3R,1S-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3R,1S-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3R,1S-5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3R,1S-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-8-trifluoromethyl-3-quinolinecarboxylicacid,

3R,1S-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-5-methyl-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3R,1S-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-1,8-naphthyridine-3-carboxylicacid,

3R,1S-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3R,1S-5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3R,1S-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3R,1S-1-cyclopropyl-8-ethoxy-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3R,1S-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,

3R,1S-8-chloro-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1S-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid,

3R,1S-5-amino-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1S-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1S-5-amino-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid,

3R,1S-1-(2,4-difluorophenyl)-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid,

3R,1S-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-8-trifluoromethyl-3-quinolinecarboxylicacid,

3R,1S-1-(2,4-difluorophenyl)-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1S-1-(2,4-difluorophenyl)-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,

3R,1S-5-amino-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1S-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid,

3R,1S-1-cyclopropyl-8-ethoxy-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1S-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,

3R,1S-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid,

3R,1S-5-amino-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1S-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1S-8-chloro-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1S-5-amino-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid,

3R,1S-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-trifluoromethyl-4-oxo-3-quinolinecarboxylicacid,

3R,1S-1-(2,4-difluorophenyl)-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1S-1-(2,4-difluorophenyl)-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,

3R,1S-1-(2,4-difluorophenyl)-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid,

3R,1S-5-amino-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1S-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid,

3R,1S-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-8-ethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3S,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,

3S,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3S,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3S,1R-5-amino-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3S,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid,

3S,1R-5-amino-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid,

3S,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8-trifluoromethyl-3-quinolinecarboxylicacid,

3S,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid,

3S,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,

3S,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3S,1R-5-amino-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3S,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid,

3S,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-8-ethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3S,1R-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-1,8-naphthyridine-3-carboxylicacid,

3S,1R-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3S,1R-5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3S,1R-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3S,1R-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3S,1R-5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3S,1R-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-8-trifluoromethyl-3-quinolinecarboxylicacid,

3S,1R-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-5-methyl-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3S,1R-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-1,8-naphthyridine-3-carboxylicacid,

3S,1R-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3S,1R-5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3S,1R-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3S,1R-1-cyclopropyl-8-ethoxy-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3S,1R-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,

3S,1R-8-chloro-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3S,1R-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid,

3S,1R-5-amino-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3S,1R-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3S,1R-5-amino-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid,

3S,1R-1-(2,4-difluorophenyl)-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid,

3S,1R-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-8-trifluoromethyl-3-quinolinecarboxylicacid,

3S,1R-1-(2,4-difluorophenyl)-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3S,1R-1-(2,4-difluorophenyl)-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,

3S,1R-5-amino-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3S,1R-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid,

3S,1R-1-cyclopropyl-8-ethoxy-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3S,1R-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,

3S,1R-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid,

3S,1R-5-amino-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3S,1R-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3S,1R-8-chloro-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3S,1R-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid,

3S,1R-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-trifluoromethyl-3-quinolinecarboxylicacid,

3S,1R-1-(2,4-difluorophenyl)-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3S,1R-1-(2,4-difluorophenyl)-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,

3S,1R-1-(2,4-difluorophenyl)-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid,

3S,1R-5-amino-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3S,1R-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid,

3S,1R-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-8-ethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,

3R,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1R-5-amino-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid,

3R,1R-5-amino-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid,

3R,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8-trifluoromethyl-3-quinolinecarboxylicacid,

3R,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid,

3R,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,

3R,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1R-5-amino-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid,

3R,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-8-ethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1R-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-1,8-naphthyridine-3-carboxylicacid,

3R,1R-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3R,1R-5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3R,1R-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3R,1R-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3R,1R-5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3R,1R-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-8-trifluoromethyl-3-quinolinecarboxylicacid,

3R,1R-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-5-methyl-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3R,1R-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-1,8-naphthyridine-3-carboxylicacid,

3R,1R-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3R,1R-5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3R,1R-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3R,1R-1-cyclopropyl-8-ethoxy-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid,

3R,1R-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,

3R,1R-8-chloro-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1R-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid,

3R,1R-5-amino-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1R-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1R-5-amino-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid,

3R,1R-1-(2,4-difluorophenyl)-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid,

3R,1R-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-8-trifluoromethyl-3-quinolinecarboxylicacid,

3R,1R-1-(2,4-difluorophenyl)-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1R-1-(2,4-difluorophenyl)-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,

3R,1R-5-amino-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1R-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid,

3R,1R-1-cyclopropyl-8-ethoxy-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1R-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,

3R,1R-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid,

3R,1R-5-amino-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1R-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1R-8-chloro-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1R-5-amino-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid,

3R,1R-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-trifluoromethyl-3-quinolinecarboxylicacid,

3R,1R-1-(2,4-difluorophenyl)-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1R-1-(2,4-difluorophenyl)-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid,

3R,1R-1-(2,4-difluorophenyl)-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid,

3R,1R-5-amino-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

3R,1R-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid, and

3R,1R-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-8-ethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid.

Particularly valuable enantiomers of 7-[3-(1-aminoalkyl)-1-pyrrolidinesand additional novel intermediates used to prepare the 7-side chain forthe final products are:

FINAL AMINES FOR COUPLING

(3R,1'R)-3-(1'-aminoethyl)pyrrolidine

(3R,1'S)-3-(1'-aminoethyl)pyrrolidine

(3S,1'R)-3-(1'-aminoethyl)pyrrolidine

(3S,1'S)-3-(1'-aminoethyl)pyrrolidine

(3R,1'R)-3-(1'-N-methylaminoethyl)pyrrolidine

(3R,1'S)-3-(1'-N-methylaminoethyl)pyrrolidine

(3S,1'R)-3-(1'-N-methylaminoethyl)pyrrolidine

(3S,1'S)-3-(1'-N-methylaminoethyl)pyrrolidine

(3R,1'R)-3-(1'-N-ethylaminoethyl)pyrrolidine

(3R,1'S)-3-(1'-N-ethylaminoethyl)pyrrolidine

(3S,1'R)-3-(1'-N-ethylaminoethyl)pyrrolidine

(3S,1'S)-3-(1'-N-ethylaminoethyl)pyrrolidine

(3R,1'R)-3-(1'-N,N-dimethylaminoethyl)pyrrolidine

(3R,1'S)-3-(1'-N,N-dimethylaminoethyl)pyrrolidine

(3S,1'R)-3-(1'-N,N-dimethylaminoethyl)pyrrolidine

(3S,1'S)-3-(1'-N,N-dimethylaminoethyl)pyrrolidine

(3R,1'R)-3-(1'-N-t-butyloxycarbonylaminoethyl)pyrrolidine

(3R,1'S)-3-(1'-N-t-butyloxycarbonylaminoethyl)pyrrolidine

(3S,1'R)-3-(1'-N-t-butyloxycarbonylaminoethyl)pyrrolidine

(3S,1'S)-3-(1'-N-t-butyloxycarbonylaminoethyl)pyrrolidine

(3R,1'R)-3-(1'-N-methyl-N-t-butyloxycarbonylaminoethyl)pyrrolidine

(3R,1'S)-3-(1'-N-methyl-N-t-butyloxycarbonylaminoethyl)pyrrolidine

(3S,1'R)-3-(1'-N-methyl-N-t-butyloxycarbonylaminoethyl)pyrrolidine

(3S,1'S)-3-(1'-N-methyl-N-t-butyloxycarbonylaminoethyl)pyrrolidine

N1 BENZYL INTERMEDIATES

(3R,1'R)-3-(1'-aminoethyl)-1-(S-α-methylbenzyl)pyrrolidine

(3R,1'S)-3-(1'-aminoethyl)-1-(S-α-methylbenzyl)pyrrolidine

(3S,1'R)-3-(1'-aminoethyl)-1-(S-α-methylbenzyl)pyrrolidine

(3S,1'S)-3-(1'-aminoethyl)-1-(S-α-methylbenzyl)pyrrolidine

(3R,1'R)-3-(1'-N-methylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine

(3R,1'S)-3-(1'-N-methylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine

(3S,1'R)-3-(1'-N-methylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine

(3S,1'S)-3-(1'-N-methylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine

(3R,1'R)-3-(1'-N-ethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine

(3R,1'S)-3-(1'-N-ethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine

(3S,1'R)-3-(1'-N-ethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine

(3S,1'S)-3-(1'-N-ethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine

(3R,1'R)-3-(1'-N,N-dimethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine

(3R,1'S)-3-(1'-N,N-dimethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine

(3S,1'R)-3-(1'-N,N-dimethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine

(3S,1'S)-3-(1'-N,N-dimethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine

(3R,1'R)-3-(1'-N-t-butyloxycarbonylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine

(3R,1'S)-3-(1'-N-t-butyloxycarbonylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine

(3S,1'R)-3-(1'-N-t-butyloxycarbonylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine

(3S,1'S)-3-(1'-N-t-butyloxycarbonylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine

(3R,1'R)-3-(1'-N-methyl-N-t-butyloxycarbonylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine

(3R,1'S)-3-(1'-N-methyl-N-t-butyloxycarbonylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine

(3S,1'R)-3-(1'-N-methyl-N-t-butyloxycarbonylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine

(3S,1'S)-3-(1'-N-methyl-N-t-butyloxycarbonylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine

(3R,1'R)-3-(1'-aminoethyl)-1-(R-α-methylbenzyl)pyrrolidine

(3R,1'S)-3-(1'-aminoethyl)-1-(R-α-methylbenzyl)pyrrolidine

(3S,1'R)-3-(1'-aminoethyl)-1-(R-α-methylbenzyl pyrrolidine

(3S,1'S)-3-(1'-aminoethyl)-1-(R-α-methylbenzyl)pyrrolidine

(3R,1'R)-3-(1'-N-methylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidine

(3R,1'S)-3-(1'-N-methylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidine

(3S,1'R)-3-(1'-N-methylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidine

(3S,1'S)-3-(1'-N-methylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidine

(3R,1'R)-3-(1'-N-ethylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidine

(3R,1'S)-3-(1'-N-ethylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidine

(3S,1'R)-3-(1'-N-ethylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidine

(3S,1'S)-3-(1'-N-ethylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidine

(3R,1'R)-3-(1'-N,N-dimethylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidine

(3R,1'S)-3-(1'-N,N-dimethylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidine

(3S,1'R)-3-(1'-N,N-dimethylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidine

(3S,1'S)-3-(1'-N,N-dimethylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidine

(3R,1'R)-3-(1'-N-t-butyloxycarbonylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidine

(3R,1'S)-3-(1'-N-t-butyloxycarbonylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidine

(3S,1'R)-3-(1'-N-t-butyloxycarbonylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidine

(3S,1'S)-3-(1'-N-t-butyloxycarbonylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidine

(3R,1'R)-3-(1'-N-methyl-N-t-butyloxycarbonylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidine

(3R,1'S)-3-(1'-N-methyl-N-t-butyloxycarbonylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidine

(3S,1'R)-3-(1'-N-methyl-N-t-butyloxycarbonylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidine

(3S,1'S)-3-(1'-N-methyl-N-t-butyloxycarbonylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidine

PYRROLIDINONES

(3R,1'R)-3-(1'-aminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3R,1'S)-3-(1'-aminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3S,1'R)-3-(1'-aminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3S,1'S)-3-(1'-aminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3R,1'R)-3-(1'-N,N-dimethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3R,1'S)-3-(1'-N,N-dimethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3S,1'R)-3-(1'-N,N-dimethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3S,1'S)-3-(1'-N,N-dimethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3R,1'R)-3-(1'-N-acetylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3R,1'S)-3-(1'-N-acetylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3S,1'R)-3-(1'-N-acetylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3S,1'S)-3-(1'-N-acetylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3R,1'R)-3-(1'-N-t-butyloxycarbonylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one(3R,1'S)-3-(1'-N-t-butyloxycarbonylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3S,1'R)-3-(1'-N-t-butyloxycarbonylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3S,1'S)-3-(1'-N-t-butyloxycarbonylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3R,1'R)-3-(1'-aminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3R,1'S)-3-(1'-aminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3S,1'R)-3-(1'-aminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3S,1'S)-3-(1'-aminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3R,1'R)-3-(1'-N,N-dimethylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3R,1'S)-3-(1'-N,N-dimethylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3S,1'R)-3-(1'-N,N-dimethylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3S,1'S)-3-(1'-N,N-dimethylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3R,1'R)-3-(1'-N-acetylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3R,1'S)-3-(1'-N-acetylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3S,1'R)-3-(1'-N-acetylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3S,1'S)-3-(1'-N-acetylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3R,1'R)-3-(1'-N-t-butyloxycarbonylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3R,1'S)-3-(1'-N-t-butyloxycarbonylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3S,1'R)-3-(1'-N-t-butyloxycarbonylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3S,1'S)-3-(1'-N-t-butyloxycarbonylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

OXIMES

3R-3-(1'-hydroxyaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

3S-3-(1'-hydroxyaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

3R-3-(1'-hydroxyaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

3S-3-(1'-hydroxyaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

KETONES

3-(acetyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

3-(acetyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

3R-3-(acetyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

3S-3-(acetyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

3R-3-(acetyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

3S-3-(acetyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

BETA KETO ESTERS

3-(2'-(ethoxycarbonyl)acetyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

3-(2'-(ethoxycarbonyl)acetyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

3R-3-(2'-(ethoxycarbonyl)acetyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

3S-3-(2'-(ethoxycarbonyl)acetyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

3R-3-(2'-(ethoxycarbonyl)acetyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

3S-3-(2'-(ethoxycarbonyl)acetyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

OTHER COMPOUNDS POSSIBLE

(3R,1'R)-3-(1'-N-t-butyloxycarbonyl-N-methylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3R,1'S)-3-(1'-N-t-butyloxycarbonyl-N-methylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3S,1'R)-3-(1'-N-t-butyloxycarbonyl-N-methylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3S,1'S)-3-(1'-N-t-butyloxycarbonyl-N-methylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3R,1'R)-3-(1'-N-t-butyloxycarbonyl-N-methylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3R,1'S)-3-(1'-N-t-butyloxycarbonyl-N-methylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3S,1'R)-3-(1'-N-t-butyloxycarbonyl-N-methylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3S,1'S)-3-(1'-N-t-butyloxycarbonyl-N-methylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3R,1'R)-3-(1'-N-trifluoroacetyl-N-methylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3R,1'S)-3-(1'-N-trifluoroacetyl-N-methylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3S,1'R)-3-(1'-N-trifluoroacetyl-N-methylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3S,1'S)-3-(1'-N-trifluoroacetyl-N-methylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3R,1'R)-3-(1'-N-trifluoroacetyl-N-methylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3R,1'S)-3-(1'-N-trifluoroacetyl-N-methylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3S,1'R)-3-(1'-N-trifluoroacetyl-N-methylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3S,1'S)-3-(1'-N-trifluoroacetyl-N-methylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3R,1'R)-3-(1'-N-trifluoroacetylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3R,1'S)-3-(1'-N-trifluoroacetylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3S,1'R)-3-(1'-N-trifluoroacetylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3S,1'S)-3-(1'-N-trifluoroacetylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one

(3R,1'R)-3-(1'-N-trifluoroacetylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3R,1'S)-3-(1'-N-trifluoroacetylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3S,1'R)-3-(1'-N-trifluoroacetylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

(3S,1'S)-3-(1'-N-trifluoroacetylaminoethyl)-1-(R-α-methylbenzyl)pyrrolidin-5-one

The final products and intermediates of the present invention may beprepared as detailed hereafter and as illustrated by the followingschemes. ##STR14##

DETAILED DESCRIPTION

Starting from the previously prepared (J. Med. Chem., (1987), 30, 1711)1-(S-α-methylbenzyl)-pyrrolidin-5-one-3-carboxylic acid (1) conversionto an activated intermediate (2) is preferably done by reaction withcarbonyl diimidazole in THF at 30°-50° C. for 18-30 hours, Equation 1.Alternative solvents include diethylether, dioxane and the like,chlorocarbon solvents, toluene or other aromatic solvents at roomtemperature to 100° C. for 1-72 hours. Alternative methods of carboxylicacid activation such as conversion to an acid chloride with thionylchloride, phosphorus oxychloride, or the like or activation byconversion to a mixed anhydride with trifluoroacetic anhydride or thelike are also suitable. The activated acid (2) is reacted in situ,preferably, or after isolation with an anion of diethylmalonate,preferably magnesium bis(ethylmalonate) (3) in THF at reflux temperaturefor 2-4 hours. The solvents employed above are also acceptable for thisstep at ambient temperatures to 150° C. The use of dilithioethylmalonate, or the anion of diethylmalonate (cation=lithium,magnesium, sodium, calcium, or potassium) are also acceptable. In situdecarboxylation is accomplished next through the use of an aqueousworkup or if desired an acidic workup to give3-(2'-(ethoxycarbonyl)acetyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one (4).Acids useful for affecting decarboxylation are HCl, H₂ SO₄, H₃ PO₄ andthe like, Equation 1.

This β-keto ester (4) is reacted preferably with sodium chloride in DMSOcontaining 100-1000 mol % water at 120°-220° C. to affectdecarboxylation, preferably 200-400 mol % of NaCl at 103°-140° C. for18-24 hours, giving 3-(acetyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one (5),Equation 2.

The methyl ketone (5) was converted to3-(1'-hydroxyiminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one (6 and 7 )via reaction with hydroxylamine hydrochloride in a suitable solvent atambient temperature to 100° C. Preferably this is performed inethanol/water at 40° C. to ambient temperature. Solvents such aspyridine, THF, and other alcohol solvents are also useful for thepreparation of the oxime. The oxime (6 and 7) is separated into itsindividual diastereomers (6) and (7) by column chromatography on silicagel (70-230 or 230-400 mesh) using ethyl acetate, ethylacetate-saturated hydrocarbon solvent, such as pentane, hexane, heptane,and isooctane. Final purification is through recrystallization of thepurified diastereomers3S-3-(1'-hydroxyiminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one (6) and3R-3-(1'RS-hydroxyiminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one (7)from ethyl acetate or a like solvent.

The individual oxime (7) is reduced to the primary amines,(3R,1RS)-3-(1'-aminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one (8 and9) through the use of catalytic hydrogenation with hydrogen gas(Equation 4) or a hydrogen source such as ammonium formate, cyclohexene,or cyclohexadiene. The preferred catalysts being platinum oxide, varyingpercentages of rhodium on an inert support such as carbon, alumina, orRaney-nickel, or the like, in solvents such as methanol, ethanol, THF,ethyl acetate and the like at ambient temperatures to 40°-60° C.,preferably at room temperature. The reduction produced a set ofdiastereomers (8 and 9) which were separated by column chromatography onsilica gel (70-230 or 230-400 mesh) using a chlorocarbon solventcontaining varying concentrations of a tertiary amine and an alcohol,preferably chloroform-triethylamine-ethanol giving3R,1'S-3-(1'-aminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one (8) and3R,1'R-3-(1'-aminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one (9 ),(Equation 4 ).

Likewise the oxime (6) could be reduced to give3S,1'RS-(1'-aminoethyl)-1-(S-α-methylbenzyl)-2pyrrolidin-5-one (10 and11), Equation 4.

The individual diastereomeric pyrrolidone amines (8,9,10,11) werereduced to the pyrrolidines through the action of a hydride reducingagent in an inert solvent at an elevated temperature, usually lithiumaluminum hydride in an ether solvent such as THF at 50°-66° C. or thelike, Equation 5. The primary amines (12, 13, 14, 15) individually wereeach protected as the t-butylcarbamate by reaction of the amine with at-butyloxycarbonyl transfer reagent such as di-t-butylcarbonate and thelike, Equation 6, giving 16, 17, 18, 19.

The BOC-protected aminoethylpyrrolidine (16-19) were subjected tovarying de-α-methylbenzylations via hydrogenolysis using varyingpercentages of palladium on a inert support such as carbon, alumina,silica, or the like, preferably 20% palladium on carbon in an inertsolvent such as methanol, ethanol, THF, or ethyl acetate. This providesthe individual diastereomeric 3-(1'-aminoethyl)pyrrolidines (20, 21, 22,23), (Equation 7) in a protected form suitable for coupling with aquinolone or naphthyridone substrate.

The individual 3-(1'-N,N-dimethylaminoethyl)pyrrolidines (32, 33, 34,35) could be prepared by reacting the amine (8, 9, 10, 11) withparaformaldehyde in formic acid at an elevated temperature, preferablyemploying aqueous solutions of formaldehyde (20-80%, usually 35%) andaqueous formic acid (50-90%, usually 88%) beginning at 0°-5° C. andcontinuing at reflux temperature for 2-10 hours (preferably five hours).This provides the individual diastereomeric N,N-dimethylamines (24, 25,26, 27), Equation 8. The carbonyl function of 24-27 was removed byreducing the pyrrolidin-5-one with a hydride reducing agent in an inertsolvent. The preferred method was with lithium aluminum hydride in THFat reflux for 12-24 hours giving the pyrrolidines 28, 29, 30, 31,Equation 9. The 3-(1'-N,N-dimethylaminoethyl)pyrrolidines (28-31) werede-α-methylbenzylated via hydrogenolysis using varying percentages ofpalladium on a inert support such as carbon, alumina, silica, or thelike, preferably 20% palladium on carbon in an inert solvent such asmethanol, ethanol, THF, or ethyl acetate. This provides the individualdiastereomeric 3-(1'-N,N-dimethylaminoethyl)pyrrolidines, 32, 33, 34,35, (Equation 10) in a form suitable for coupling with a quinolone ornaphthyridone substrate.

The 3-(1'-N-ethylaminoethyl)pyrrolidines (44, 45, 46, 47) were preparedby reacting the amines (8, 9, 10, 11) with an acetyl transfer agent suchas acetic anhydride or acetyl chloride or the like in the presence of anacid scavenger such as a tertiary amine including pyridine, lutidine,triethylamine and the like either with or without an inert solvent suchas an ether or chlorocarbon in a temperature range of room temperatureto the reflux temperature of the reaction mixture for 6-72 hours,preferable in acetic anhydride-pyridine 4/1 at ambient temperature for12-24 hours to give the 3-(N-acetyl-1'-aminoethyl)pyrrolidin-5-ones, 36,37, 38, 39, Equation 11. The two amide functions of 36-39 were reducedby reacting the pyrrolidin-5-one with a hydride reducing agent in aninert solvent. The preferred method was with lithium aluminum hydride inTHF at reflux for 12-24 hours giving the individual diastereomericpyrrolidines, 40, 41,42,43, Equation 12. The individual diastereomeric3-(1'-N-ethylaminoethyl)-(1-α-methylbenzyl)pyrrolidines (40-43) werede-α-methylbenzylated via hydrogenolysis using varying percentages ofpalladium on an inert support such as carbon, alumina, silica, or thelike, preferably 20% palladium on carbon in an inert solvent such asmethanol, ethanol, THF, or ethyl acetate. This provides the individual3-(1'-N-ethylaminoethyl)pyrrolidines, 44, 45, 46, 47, (Equation 13) in aform suitable for coupling with a quinolone or naphthyridone substrate.

The 3-(N-t-butyloxycarbonyl-1'-N-methylaminoethyl)pyrrolidines (60, 61,62, 63) were prepared by reacting the amines (8-11) with at-butyloxycarbonyl transfer agent such as di-t-butylcarbonate ort-butyloxycarbonyl chloride or the like in the presence of an acidscavenger such as a tertiary amine including pyridine, lutidine,triethylamine and the like either with or without an inert solvent suchas an ether or chlorocarbon in a temperature range of room temperatureto the reflux temperature of the reaction mixture for 6-72 hours,preferable in dichloromethane and di-t-butylcarbonate at ambienttemperature for 12-24 hours to give the3-(N-t-butyloxycarbonyl-1'-aminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-ones,48, 49, 50, 51, Equation 14. The two amides were removed by reacting thepyrrolidin-5-ones (48-51) with a hydride reducing agent in an inertsolvent. The preferred method was with lithium aluminum hydride in THFat reflux for 12-24 hours giving the individual diastereomericpyrrolidines, 52, 53, 54, 55, Equation 15. The reduced pyrrolidines,52-55, could be protected by reacting the 3-N-methyl-1'-aminomethylmoiety with a t-butyloxycarbonyl transfer agent such asdi-t-butylcarbonate or t-butyloxycarbonyl chloride or the like in thepresence of an acid scavenger such as a tertiary amine includingpyridine, lutidine, triethylamine and the like either with or without aninert solvent such as an ether or chlorocarbon in a temperature range ofroom temperature to the reflux temperature of the reaction mixture for6-72 hours, preferably in dichloromethane and di-t-butyldicarbonate atambient temperature for 12-24 hours to give the1-(α-methylbenzyl)-3-(N-t-butyloxycarbonyl-1'-N-methylaminoethyl)pyrrolidines,56, 57, 58, 59, Equation 16. The3-(N-t-butyloxycarbonyl-1'-N-methylaminoethyl)pyrrolidines, 56-59 werede-α-methylbenzylated via hydrogenolysis using varying percentages ofpalladium on an inert support such as carbon, alumina, silica, or thelike, preferably 20% palladium on carbon in an inert solvent such asmethanol, ethanol, THF, or ethyl acetate. This provides the3-(1'-N-t-butoxycarbonyl-1'-N-methylaminoethyl)pyrrolidines, 60, 61, 62,63 (Equation 17) in a form suitable for coupling with a quinolone ornaphthyridone nucleus.

The 3-(1'-N-methylaminoethyl)pyrrolidines, 64-67, were prepared by thede-α-methylbenzylation, via hydrogenolysis using varying percentages ofpalladium on an inert support such as carbon, alumina, silica, or thelike, preferably 20% palladium on carbon in an inert solvent such asmethanol, ethanol, THF, or ethyl acetate, of the pyrrolidines, 52, 53,54, 55, Equation 18. This provides the individual diastereomers 64, 65,66, 67, 3-(1'-N-methylaminoethyl)pyrrolidines (Equation 18) in a formsuitable for coupling with a quinolone or naphthyridone substrate.

Alternatively, the 3-(1'-aminoethyl)pyrrolidin-5-one (8 and 9) werereacted with methyl trifluoroacetate in an inert solvent oralternatively with trifluoroacetic anhydride in the presence of an acidacceptor such as triethylamine or pyridine or the like at 0° C. toambient temperature to give the3-(N-trifluoroacetyl-1'-aminoethyl)pyrrolidin-5-ones, 68, Equation 19.These compounds were reacted with a hydrogen abstractor such as sodiumhydride or a similar agent in an ether solvent such as THF followed byaddition of a methylating agent like methyliodide to give the3-(N-methyl-N-trifluoroacetyl-1'-aminoethyl)pyrrolidin-5-one, 69,Equation 20. The trifluoroacetyl group could be removed by hydrolysisusing aqueous hydroxide, Equation 21. The resulting compounds 70 couldbe reduced as described above.

The pyrrolidines prepared could be coupled to the appropriate quinoloneor naphthyridone substrate by published procedures including; Domagala,et al., J. Medicinal Chemistry, 31, 503 (1988), Sanchez, et al., J.Medicinal Chemistry, 31, 983, (1988), Itawa, et al., European PatentApplication 8702813.8 1987, and British Patent 2,011,395A.

A representative group of quinolones is shown in FIG. 1. ##STR15##

The enantiomeric quinolones and naphthyridones of the invention displaypotent antibacterial activity against gram negative and especially grampositive organisms both in vitro as well as in vivo. Their overalltherapeutic advantages are also shown by including phototoxicity andcytotoxicity data as compared to compounds described in European PatentPublication 207,420.

The in vitro antibacterial activity, is obtained by the microtitrationdilution method as described in Heifetz, et al., Antimicr. Agents &Chemother., 6, 124 (1974), which is incorporated herein by reference.

The in vivo activity is obtained when the compounds are tested accordingto the procedure of Miller, et al (Proc. Soc. Exp. Biol. Med. 57, 261,1944). The median protective dose (PD₅₀) was determined in mice givenlethal systemic infections. Single doses of compound were given at timeof challenge.

The phototoxicity data is obtained using depilated mice. The compoundwas administered orally each day for four successive days, followed eachday by 3 hours of UVA radiation. The mice were examined for any positivesigns (redness, erythema) relative to control animals. The no effectdose and the 50% effect dose were determined.

The cytotoxicity data is obtained using hamster V-79 cells. The cellswere suspended in tissue culture medium and grown overnight. Cells weretreated with drug for 3 hours, washed free of drug and then replated,and the colonies counted after 5 days. The concentration of drug thatreduced colones by 50% relative to control was recorded.

By use of the above methods, the following minimum inhibitingconcentration values (MICs in μg/mL), PD₅₀ 's in mg/kg, no effectphototoxicity dose in mg/kg and the cytotoxicity IC₅₀ in μg/mL wereobtained for representative enantiomers of the invention and compoundsof the prior art as shown in the table.

The in vivo data as PD₅₀ s are reported below the line of MICs for thesame compound.

      -  Ent. Esch. Klebs. Prot. Pseud. Staph. Staph. Strep. Strep. Strep.     Photo       cloacae coli pneumoniae rettgeri aeruginosa aureus aureus faecalis     pheumoniae pyogenes NED Cytotox      Example Number MA2646 Vogel MGH-2 M 1771 UI-18 H 228 UC-76 MGH-2 SV-1     C-203 mg/kg μg/mL      2 0.2 0.2 0.4 0.8 1.5 0.8 0.1 0.4 0.2 0.1  160       PO 100       >100       SC 4       12      1 0.2 0.2 0.4 0.8 1.5 0.4 0.05 0.2 0.1 0.1  160       PO 35       >100       SC 2       3      3 0.05 0.05 0.1 0.2 0.4 0.05 0.003 0.025 0.003 0.003  42       PO 47       11       SC 0.9       0.7      4 0.2 0.1 0.4 0.8 1.6 0.2 0.05 0.1 0.025 0.1  140       PO 72       105       SC 2       2      Enantiomer Mixture 0.1 0.05 0.2 0.4 1.6 0.1 0.013 0.05 0.006 0.006  60       (Mixture B) PO 29       12       SC 2       1      5 0.05 0.05 0.1 0.2 0.8 0.2 0.025 0.1 0.05 0.05 >100 84       PO 4   23    15       SC 1   16    7      6 0.05 0.05 0.2 0.4 1.6 0.2 0.025 0.1 0.05 0.05 >100 77       PO 8   96    28       SC 1   25    10      7 0.025 0.025 0.05 0.1 0.4 0.025 0.03 0.025 0.006 0.013 30 33       PO 2   15    3 3       SC 0.4   4    1 1      8 0.05 0.05 0.1 0.4 0.8 0.05 0.06 0.05 0.006 0.013 55 100       PO 6   35    14       SC 1   12    2      ##STR16##      0.05POSC 0.02520.8 0.1 0.2 0.8166 0.05 0.006 0.05 0.01352 0.01341 55 48     Reference Example 5 0.4 0.05 0.2 0.4 1.6 0.1 0.013 0.05 0.013 0.05  150       EPO 207420 PO 9      (Mixture C) SC 2      24 0.4 0.2 0.4 0.8 3.1 0.8 0.2 0.8 0.4 0.4      23 0.1 0.1 0.2 0.8 1.6 0.2 0.05 0.2 0.1 0.1      21 0.1 0.1 0.2 0.4 1.6 0.05 0.0013 0.05 0.013 0.025  130       PO 1.0        2       SC 0.5        2      22 0.1 0.1 0.2 0.4 1.6 0.1 0.05 0.025 0.05 0.05  88       PO 4.6        8       SC 1.2        5      ##STR17##      0.05POSC 0.0541 0.1 0.8 1.6 0.1 0.025 0.1 0.05 0.1116  140     42 0.025 0.025 0.05 0.1 0.8 0.006 0.003 0.013 0.006 0.006 <30 17               PO 3        0.55       SC 0.4        0.25      41 0.05 0.05 0.1 0.2 0.8 0.006 0.003 0.013 0.006 0.006 30 33       PO 3        2       SC 2        0.7      81 0.8 0.4 0.8 3.1 6.3 0.8 0.4 0.8 0.2 0.4      80 0.2 0.2 0.4 1.6 3.1 0.2 0.1 0.2 0.1 0.4      79 0.1 0.1 0.2 0.8 1.6 0.1 0.025 0.05 0.025 0.05       PO 2        2       SC 1        2      78 0.4 0.1 0.2 1.6 1.6 0.05 0.025 0.05 0.025 0.05       PO         6       SC         4      20 0.8 0.8 1.6 3.1 6.3 0.2 0.05 0.4 0.2 0.2      19 0.4 0.4 0.8 1.6 6.3 0.1 0.05 0.1 0.013 0.025      18 0.1 0.1 0.2 0.4 3.1 0.013 0.003 0.025 0.005 0.006 >100 110       PO 5        0.5       SC 2        0.2      17 0.2 0.2 0.4 0.8 3.1 0.013 0.003 0.013 0.003 0.003 >100 130       PO 14        2       SC 4        0.6      36 0.05 0.05 0.1 0.2 0.8 0.013 0.013 0.025 0.013 0.003 >100 33       PO 4        1       SC 1        0.1      38 0.2 0.2 0.4 0.8 3.1 0.05 0.013 0.05 0.025 0.025 -- 130       PO         6       SC         1      44 0.05 0.025 0.05 0.05 0.4 0.006 ≦0.003 0.006 ≦0.003     ≦0.003      45 0.05 0.05 0.1 0.2 0.8 0.25 ≦0.03 0.025 0.013 0.013      46 0.2 0.2 0.4 0.4 1.6 0.025 0.013 0.1 0.013 0.013      47 0.1 0.1 0.1 0.2 0.8 0.025 0.003 0.025 0.003 0.003      48 0.1 0.1 0.2 0.4 1.6 0.1 0.025 0.1 0.05 0.05       PO         9       SC         3      49 0.2 0.1 0.2 0.2 1.6 0.013 ≦0.003 0.025 0.006 0.006      43 0.2 0.1 0.2 0.4 0.8 0.05 0.006 0.025 0.006 0.006 >100 280       PO 3.5       3 1       SC 1       3 1      50 0.8 0.4 0.8 1.6 3.1 0.05 0.013 0.2 0.1 0.1       PO        2       SC        2      51 0.8 0.8 1.6 3.1 >3.1 0.2 0.05 0.4 0.2 0.2      52 0.4 0.4 0.4 1.6 3.1 0.05 0.013 0.05 0.05 0.05      53 0.025 0.025 0.05 0.1 0.8 ≦0.003 ≦0.003 0.013 ≦0.     003 ≦0.003       PO 1.6        0.3       SC 0.8        0.3      54 0.4 0.4 0.8 1.6 3.1 0.025 0.013 0.1 0.013 0.013      55 0.1 0.1 0.2 0.8 1.6 0.05 0.025 0.05 0.013 0.013 --      56 0.2 0.1 0.2 0.4 1.6 0.013 0.006 0.025 0.006 0.006      57 0.4 0.4 0.4 0.8 3.1 0.025 0.013 0.05 0.025 0.025  220      58 0.013 0.013 0.013 0.025 0.4 0.003 0.003 0.003 0.003 0.003      59 0.05 0.05 0.1 0.1 0.8 0.006 0.003 0.006 0.003 0.003      60 0.2 0.2 0.2 0.4 1.6 0.013 0.006 0.025 0.006 0.006      61 0.1 0.1 0.2 0.4 1.6 0.006 ≦0.003 0.025 ≦0.003 ≦0     .003      34 0.4 0.4 0.8 1.6 3.1 0.8 0.4 1.6 0.8 1.6      35 0.2 0.2 0.8 0.8 3.1 0.1 0.05 0.2 0.2 0.2      63 0.4 0.4 0.4 0.8 3.1 0.1 0.05 0.2 0.2 0.2      64 0.8 0.4 0.8 1.6 3.1 0.1 0.025 0.2 0.025 0.05  310       PO 5        4       SC 2        2      65 0.1 0.1 0.2 0.4 0.8 0.013 0.006 0.025 0.003 0.003  10       PO         5       SC         0.6      67 0.4 0.8 1.6 3.1 0.05 0.013 0.1 0.013 0.025       PO         29       SC         3      69 0.1 0.1 0.2 0.4 1.6 0.05 0.006 0.025 0.013 0.025      70 0.4 0.4 0.8 3.1 12.5 0.4 0.2 0.8 0.2 0.4      72 0.2 0.1 0.2 0.8 1.6 0.025 0.025 0.1 0.025 0.05 <30 120       PO 1   17    2 2       SC 1   11    2 2      73 0.2 0.1 0.2 0.8 1.6 0.1 0.05 0.1 0.05 0.05 <30       PO 5        4       SC 4        4

The compounds of the invention are capable of forming bothpharmaceutically acceptable acid addition and/or base salts. Base saltsare formed with metals or amines, such as alkali and alkaline earthmetals or organic amines. Examples of metals used as cations are sodium,potassium, magnesium, calcium, and the like. Also included are heavymetal salts such as for example silver, zinc, cobalt, and cerium. Suchheavy metal salts are effective in the treatment of burns especiallywhen applied to the affected surface of a burn victim either directly orin combination with a physiologically acceptable carrier such as a waterdispersible, hydrophilic carrier. Examples of suitable amines are N,N'dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, N-methylglucamine, and procaine.

Pharmaceutically acceptable acid addition salts are formed with organicand inorganic acids.

Examples of suitable acids for salt formation are hydrochloric,sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic,gluconic, fumaric, succinic, ascorbic, maleic, methanesulfonic, and thelike. The salts are prepared by contacting the free base form with asufficient amount of the desired acid to produce either a mono or di,etc. salt in the conventional manner. The free base forms may beregenerated by treating the salt form with a base. For example, dilutesolutions of aqueous base may be utilized. Dilute aqueous sodiumhydroxide, potassium carbonate, ammonia, and sodium bicarbonatesolutions are suitable for this purpose. The free base forms differ fromtheir respective salt forms somewhat in certain physical properties suchas solubility in polar solvents, but the salts are otherwise equivalentto their respective free base forms for purposes of the invention. Useof excess base where R₂ is hydrogen gives the corresponding basic salt.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms. In general, the solvatedforms, including hydrated forms and the like are equivalent to theunsolvated forms for purposes of the invention.

The compounds of the invention can be prepared and administered in awide variety of oral, parenteral and topical dosage forms. It will beobvious to those skilled in the art that the following dosage forms maycomprise as the active component, either a compound of formula I or acorresponding pharmaceutically acceptable salt of a compound of formulaI.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets, suppositories, andointments. A solid carrier can be one or more substances which may alsoact as diluents, flavoring agents, solubilizers, lubricants, suspendingagents, binders, or tablet-disintegrating agents; it can also be anencapsulating material. In powders, the carrier is a finely dividedsolid which is in admixture with the finely divided active compound. Inthe tablet the active compound is mixed with carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired. The powders and tablets preferably containfrom 5 or 10 to about 70% of the active ingredient. Suitable solidcarriers are magnesium carbonate, magnesium stearate, talc, sugar,lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose,sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and thelike. The term "preparation" is intended to include the formulation ofthe active compound with encapsulating material as carrier providing acapsule in which the active component (with or without other carriers)is surrounded by carrier, which is thus in association with it.Similarly, cachets are included. Tablets, powders, cachets, and capsulescan be used as solid dosage forms suitable for oral administration.

Liquid form preparations include solutions suspensions and emulsions. Anexample may be water or water-propylene glycol solutions for parenteralinjection. Such solutions are prepared so as to be acceptable tobiological systems (isotonicity, Ph, etc.). Liquid preparations can alsobe formulated in solution in aqueous polyethylene glycol solution.Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing, and thickening agents as desired. Aqueous suspensionsuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, i.e., natural orsynthetic gums, resins, methyl cellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

Ointment preparations contain heavy metal salts of a compound of formulaI with a physiologically acceptable carrier. The carrier is desirably aconventional water-dispersible hydrophilic or oil-in-water carrier,particularly a conventional semi-soft or cream-like water-dispersible orwater soluble, oil-in-water emulsion which may be applied to an affectedburn surface or infected surface with a minimum of discomfort. Suitablecompositions may be prepared by merely incorporating or homogeneouslyadmixing finely divided compounds with the hydrophilic carrier or baseor ointment.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, for example, packeted tablets, capsules, powders in vialsor ampoules, and ointments in tubes or jars. The unit dosage form canalso be a capsule, cachet, tablet, gel or cream itself or it can be theappropriate number of any of these packaged forms.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from 1 mg to 100 mg according to the particularapplication and the potency of the active ingredient.

In therapeutic use as agents for treating bacterial infections, thecompounds utilized in the pharmaceutical method of this invention areadministered at the initial dosage of about 3 mg to about 40 mg perkilogram daily. A daily dose range of about 6 mg to about 14 mg perkilogram is preferred. The dosages, however, may be varied dependingupon the requirements of the patient, the severity of the conditionbeing treated, and the compound being employed. Determination of theproper dosage for a particular situation is within the skill of the art.Generally, treatment is initiated with smaller dosages which are lessthan the optimum dose of the compound. Thereafter, the dosage isincreased by small increments until the optimum effect under thecircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day if desired.

The following nonlimiting examples illustrate the inventors' preferredmethods for preparing the compounds of the invention.

PREPARATION OF INTERMEDIATES EXAMPLE A(3R,1'S)-3-(1'-N-acetylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one,36

(3R,1'S)-3-(1'-Aminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one, 8,(10.0 g, 0.043 mol) was dissolved in pyridine (50 mL) and aceticanhydride (250 mL) and stirred for 18 hours, then evaporated to an oil.This oil was purified by column chromatography using methylene chloridemethanol (20/1) to give the title compound as a very viscous oil,yield=9.2 g.

Calculated for C₁₆ H₂₂ N₂ O₂.0.3 C₂ H₆ O₁.0.2 H₂ O C, 68.33; H, 8.36; N,9.60 Found: C, 68.37; H, 8.09; N, 9.57.

[α]_(D) =-165° (C=0.4%, CHCl₃).

¹ H-NMR (CDCl₃) δ7.4-7.2 (m, 5H), 5.49 (q, 1H, J=9.1 Hz), 5.1-5.05(broad m, 1H) 4.0-3.85 (m, 1H), 3.39 (dd, 1H, J=8.2, 11.2 Hz), 2.78 (dd,1H, J=5.8, 10.3 Hz), 2.6-2.36 (m, 2H), 2.25-2.15 (m, 1H), 1.88 (s, 3H),1.52 (d, 3H, J=7.2 Hz), 0.97 (d, 3H, J=6.7 Hz).

EXAMPLE A-1(3R,1'R)-3-(1'-N-acetylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one,37

The procedure described above was employed to give 8.3 g of the titlecompound.

Calculated for C₁₆ H₂₂ N₂ O₂ : C, 70.04; H, 8.08; N, 10.21 Found: C,70.08; H, 8.10; N, 10.23.

[α]_(D) =-120° (C=1.1%, CHCl₃).

¹ H-NMR (CDCl₃) δ7.4-7.2 (m, 5H), 5.85-5.75 (broad m, 1H), 5.47 (q, 1H,J=7.1 Hz), 4.05-3.90 (m, 1H), 3.40-3.30 (m, 1H), 2.80-70 (m, 1H),2.55-2.20 (m, 3H), 1.84 (s, 3H), 1.52 (d, 3H, J=7.0 Hz), 0.99 (d, 3H,J=6.7 Hz).

EXAMPLE A-2(3S,1'S)-3-(1'-N-acetylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one,38

The procedure described above was employed to give 9.5 g of the titlecompound.

Calculated for C₁₆ H₂₂ N₂ O₂ : C, 70.04; H, 8.08; N, 10.21 Found: C,70.09; H, 8.01; N, 9.84.

¹ H-NMR (CDCl₃) δ7.4-7.2 (m, 5H), 6.25-6.1 (broad d, 1H), 5.46 (q, 1H,J=7.1 Hz), 4.15-4.05 (m, 1H), 3.20-2.95 (m, 2H), 2.55-2.20 (m, 3H), 1.98(s, 3H), 1.49 (d, 3H, J=7.1 Hz), 1.09 (d, 3H, J=6.7 Hz).

EXAMPLE A-3(3S,1'R)-3-(1'-N-acetylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one,39

The procedure described above was employed to give 7.4 g of the titlecompound.

Calculated for C₁₆ H₂₂ N₂ O₂.0.27 H₂ O: C, 68.82; H, 8.14; N, 10.03Found: C, 68.87; H, 8.27; N, 9.65.

¹ H-NMR (CDCl₃) δ7.4-7.2 (m, 5H), 5.85-5.75 (broad d, 1H), 5.46 (q, 1H,J=7.1 Hz), 4.05-3.95 (m, 1H), 3.25-3.15 (m, 1H), 3.10-2.95 (m, 1H),2.55-2.40 (m, 1H), 2.30-2.15 (m, 2H), 1.93 (s, 3H), 1.49 (d, 3H, J=7.0Hz), 1.11 (d, 3H, J=6.6 Hz).

EXAMPLE B(3R,1'S)-3-(1'-N-ethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine, 40

(3R,1'S)-3-(1'-N-acetylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one(9.2 g, 0.03 mol) was dissolved in THF (150 mL) and lithium aluminumhydride (2.6 g) was added portionwise. The resulting slurry was heatedat reflux for 18 hours then cooled and cautiously quenched with water(2.6 mL), 15% NaOH solution (3 mL), and water (6 mL). The resultingsuspension was filtered and evaporated to an oil. This oil was distilledat 0.1 mm Hg at 107°-112° C. to give 7.1 g of the title compound.

¹ H-NMR (CDCl₃) δ7.35 (m, 5H), 3.17 (q, 1H, J=6.7 Hz), 2.85-2.60 (m,3H), 2.60-2.45 (m, 2H), 2.20-1.85 (m, 4H), 1.50-1.30 (m, 1H overlappingwith doublet), 1.36 (d, 3H, J=6.5 Hz), 1.08-1.00 (m, 6H).

EXAMPLE B-1(3R,1'R)-3-(1'-N-ethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine, 41

Following the procedure of Example B, the(3R,1'R)-3-(1'-N-acetylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one(8.0 g, 0.029 mol) was converted to a crude oil. This oil was distilledat 0.1 mm Hg at 110° C. to give 6.1 g of the title compound.

Calculated for C₁₆ H₂₆ N₂.0.1 H₂ O: C, 77.43; H, 10.64, N, 11.29 Found:C, 77.50; H, 10.53; N, 11.56.

¹ H-NMR (CDCl₃) δ7.35-7.15 (m, 5H), 3.15 (q, 1H, J=6.6 Hz), 2.80-2.65(m, 2H), 2.60-2.40 (m, 3H), 2.40-2.30 (m, 1H), 2.20-1.90 (m, 4H),1.70-1.50 (m, 1H), 1.36 (d, 3H, J=6.6 Hz), 1.10 (t, 3H, J=7.2 Hz), 0.95(d, 3H, J=6.3 Hz).

EXAMPLE B-2(3S,1'S)-3-(1'-N-ethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine, 42

The procedure described above was employed to give 6.88 g of the titlecompound.

Calculated for C₁₆ H₂₆ N₂ : C, 77.99; H, 10.64, N, 11.37 Found: C,77.68; H, 10.58; N, 11.19.

¹ H-NMR (CDCl₃) δ7.35-7.15 (m, 5H), 3.15 (q, 1H, J=6.6 Hz), 2.80-2.65(m, 2H), 2.60-2.35 (m, 4H), 2.20-2.10 (m, 2H), 2.05-1.80 (m, 1H),1.70-1.60 (m, 1H), 1.37 (d, 3H, J=6.6 Hz), 1.10 (t, 3H, J=7.1 Hz), 0.98(d, 3H, J=6.2 Hz).

EXAMPLE B-3(3S,1'R)-3-(1'-N-ethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine, 43

The procedure described above was employed to give 5.21 g of the titlecompound.

Calculated for C₁₆ H₂₂ N₂ : C, 77.99; H, 10.64, N, 11.37 Found: C,78.22; H, 10.63; N, 11.11.

MS (EI) 245(P+), 201, 186, 174, 155, 141, 121, 105 (base), 96, 72

¹ H-NMR (CDCl₃) δ7.40-7.20 (m, 5H), 3.19 (q, 1H, J=6.5 Hz), 2.90-2.75(m, 1H), 2.75-2.65 (m, 1H), 2.60-2.45 (m, 4H), 2.25-2.10 (m, 2H),1.95-2.70 (m, 1H), 1.55-1.35 (m, 1H, overlapped with doublet), 1.37(d,3H, J=6.5 Hz), 1.15-1.00 (m, 6H).

EXAMPLE C (3R,1'R)-3-(1'-N-ethylaminoethyl)pyrrolidine, 45

(3R,1'R)-3-(1'-N-ethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine (5.4g, 0. 022 mol) was dissolved in methanol (100 mL) and 20% palladium oncarbon (1.0 g) was added. The resulting slurry was shaken under 50 psigof hydrogen for 21 hours then depressurized. The resulting suspensionwas filtered and the filtrate distilled to remove the methanol. Theremaining oil was distilled at 10-12 mm Hg at 85°-89° C. to give 2.4 gof the title compound.

¹ H-NMR (CDCl₃) δ3.10-2.85 (m, 3H), 2.80-2.70 (m, 1H), 2.65-2.50 (m,2H), 2.10-1.85 (m, 2H), 1.50-1.35 (m, 2H), 1.11 (t, 3H, J=7.0 Hz), 1.04(d, 3H, J=6.2 Hz).

EXAMPLE C-1 (3R,1'S)-3-(1'-N-ethylaminoethyl)pyrrolidine, 44

The procedure described above was followed to give 3.2 g of the titlecompound, bp 85°-92° at 10-12 mm Hg.

Calculated for C₈ H₁₈ N₂ : C, 67.55; H, 12.76; N, 19.70 Found: C, 67.58;H, 12.98; N, 19.60.

¹ H-NMR (CDCl₃) δ3.09 (dd, 1H, J=7.7, 10.6 Hz), 3.00-2.85 (m, 2H),2.80-2.45 (m, 4H), 2.05-1.80 (m, 2H), 1.50-1.30 (m, 1H), 1.15-1.00 (m,6H).

EXAMPLE C-2 (3S,1'R)-3-(1'-N-ethylaminoethyl)pyrrolidine, 47

The procedure described above was followed to give 2.38 g of the titlecompound, bp 87°-92° at 10-12 mm Hg.

Calculated for C₈ H₁₈ N₂.0.065 H₂ O: C, 67.00; H, 12.74; N, 19.35 Found:C, 67.09; H, 13.16; N, 19.35.

¹ H-NMR (CDCl₃) δ3.08 (dd, 1H, J=7.7, 10.5), 2.95-2.85 (m, 2H),2.75-2.45 (m, 5H), 2.05-1.90 (m, 1H), 1.90-1.80 (m, 1H), 1.50-1.30 (m,1H), 1.15-1.00 (m, 6H).

EXAMPLE C-3 (3S,1'S)-3-(1'-N-ethylaminoethyl)pyrrolidine, 46

The procedure described above was followed to give 3.28 g of the titlecompound, bp 88°-92° at 10-12 mm Hg.

Calculated for C₈ H₁₈ N₂ : C, 67.55; H, 12.75; N, 19.70 Found: C, 67.35;H, 13.14; N, 19.57.

¹ H-NMR (CDCl₃) δ3.10-2.85 (m, 3H), 2.80-2.55 (m, 1H), 2.50-2.40 (m,3H), 2.05-1.80 (m, 2H), 1.50-1.30 (m, 1H), 1.10 (t, 3H, J=7.3 Hz), 1.03(d, 3H, J=6.1 Hz).

EXAMPLE D1-(S-α-methylbenzyl)-3-(1'-N-methyl-N-trifluoroacetylaminoethyl)pyrrolidin-5-one,69

A methanol solution (10 mL) of1-(S-α-methylbenzyl)-3-(1'-aminoethyl)pyrrodin-5-one (8+9, 13 mmol) wastreated with methyl trifluoroacetate (1.92 g, 15 mmol) with stirring for18 hours, then was evaporated to an oil. This crude oil was dissolved inDMF and added to a suspension of NaH (0.2 g, 5 mmol, 60 wt %) in DMF (10mL). This mixture was heated to 60° C. for one hour then cooled toambient temperature. To this was added methyl iodide (0.3 mL, 5 mmol)and the reaction was stirred for 18 hours. The solvent was removed undervacuum (bath=50° C.) and the residue partitioned between methylenechloride and water. The organic layer was dried, filtered, andevaporated to give 1.5 g of the title compound, which was used withoutpurification.

EXAMPLE E1-(S-α-methylbenzyl)-3-(RS-1'-N-methylaminoethyl)pyrridin-5-one, 70

Compound 69 (1.5 g, 4.4 mmol) was dissolved in 1.0N NaOH solution (10mL) and ethanol (15 mL) and stirred at 50° C. for one hour. The solutionwas evaporated under vacuum to remove the ethanol and the residue waspartitioned between water and methylene chloride. The methylene chloridelayer was separated, the water layer was reextracted, and the combinedorganic layers were washed with water, dried, filtered and evaporated togive the title compound (0.95 g).

EXAMPLE F 3-(2'-(ethoxycarbonyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one, 4

The acid 1 (20.0 g, 85.7 mmol) was suspended in dry THF (350 mL) and thereaction was warmed to 40° C. 1,1'-carbonyldiimidazole (16.0 g, 98.6mmol) was added to the reaction in portions over 15 minutes. Thereaction was warmed to 45° C. and stirred for 24 hours. To the reactionwas added the magnesium salt, 3, (30.7 g, 107 mmol). The reaction waswarmed to reflux over 0.50 hour, refluxed 3.5 hours, then allowed tocool. The reaction was concentrated in vacuo. The residue taken up inCH₂ Cl₂ (600 mL) was washed with H₂ O (2×150 mL) followed by diluteNaHCO₃ (saturated solution diluted 10 fold, 2×200 mL). The aqueousphases were washed with CH₂ Cl₂ (2×100 mL). The organic layers werecombined and washed with saturated NaCl (3×150 mL). The combined brinelayers were washed with CH₂ Cl₂ (100 mL). All CH₂ Cl₂ layers werecombined, washed again with saturated NaCl (1×150 mL), dried with MgSO₄and concentrated to give the desired product as a brown oil (29.8 g).The crude product was chromatographed (silica gel/EtOAc) giving purediastereomers; (higher Rf diastereomer)-4 (Rf=0.45, 10.5 g, 37.6%), amixture of isomers-4 (9.68 g, 30.1%) and (lower Rf diastereomer)-4(Rf=0.30, 1.61 g, 5.6%) as viscous oils. (Higher Rf diastereomer); ¹H-NMR (CDCl₃) δ1.14-1.32 (m, 3H), 1.54 (d, J=7.1 Hz, 3H), 2.57-2.78 (m,2H), 3.05-3.24 (m, 1H), 3.30-3.46 (m, 1H), 3.48 (s, less than 2H), 3.59(dd, J=7.2, 6.4 Hz, 1H), 4.11-4.30 (m, 2H), 5.02 (s, less than 1H), 5.49(q, J=7.1 Hz, 1H), 7.22-7.43 (m, 5H), 12.19 (s, less than 1H), enoltautomer present; Anal. [C₁₇ H₂₁ NO₄ 0.27 EtOAc]

(Calc., found): C, (66.38, 66.37); H, (7.13, 7.02); N, (4.28, 4.28).

(Lower Rf diastereomer); ¹ H-NMR (CDCl₃) δ1.16-1.35 (m, 3H), 1.54 (d,J=7.1 Hz, 3H), 2.58-2.78 (m, 2H), 2.97-3.27 (m)+3.32-3.64,(m)+4.94(s)-5H total, 4.07-4.27 (m, 2H), 5.51 (q, J=7.1 Hz, 1H),7.19-7.46 (m, 5H), 12.04 (s, less than 1H), enol tautomer present; Anal.[C₁₇ H₂₁ NO₄, 0.34 EtOAc]

(Calc., found): C, (66.16, 66.08); H, (7.17, 6.80); N, (4.21, 4.20).

The isomers purified above were recombined and used in the next step.

EXAMPLE G 3-acetyl-1-(S-α-methylbenzyl)pyrrolidin-5-one, 5

The combined fractions of the above ketoester, 4, (19.9 g, 65.8 mmol)were dissolved in DMSO (84.0 mL). To the reaction was added NaCl (8.30g, 142 mmol) and H₂ O (4.38 mL, 243 mmol). The reaction was warmed to130°-135° C. for 20 hours, cooled to room temperature and partitionedbetween H₂ O (400 mL) and CH₂ Cl₂ (80 mL). The resulting layers wereseparated. The aqueous layer was washed with CH₂ Cl₂ (6×75 mL). Theorganic layers were combined, extracted with H₂ O (3×80 mL), dried withMgSO₄ and concentrated in vacuo to give crude 6 (15.9 g) as a dark oil.The crude product was chromatographed [silica gel/THF:hexane (1:1)]giving pure diastereomers.

Higher Rf diastereomer (Rf=0.22, 5.53 g, 36.3%), a mixture of isomers-(3.14, 20.6%) and lower Rf diastereomer (Rf=0.11, 6.10 g, 33.9%) asviscous oils.

Higher Rf diastereomer; ¹ H-NMR (CDCl₃) δ1.51 (d, J=7.3 Hz, 3H), 2.16(s, 3H), 2.63 (d, J=8.4 Hz, 2H), 2.97-3.30 (m, 2H), 3.40-3.63 (m, 1H),5.46 (q, J=7.3 Hz, 1H), 7.18-7.43 (m, 5H); Anal. [C₁₄ H₁₇ NO₂ ]:

(Calc., found): C, (72.70, 72.67); H, (7.41, 7.73); N, (6.06, 5.81).

Lower Rf diastereomer; ¹ H-NMR (CDCl₃) δ1.53 (d, J=7.2 Hz, 3H), 2.09 (s,3H), 2.65 (d, J=8.0 Hz, 2H), 3.08-3.38 (m, 2H), 3.47 (t, J=8.0 Hz, 1H),5.48 (q, J=7.2 Hz, 1H), 7.20-7.43 (m, 5H); Anal. [C₁₄ H₁₇ NO₂ -0.20 C₆H₁₄ ]:

(Calc., found): C, (73.46, 73.34); H, (8.03, 7.85); N, (5.64, 5.28).

The isomers purified above were combined and used in the next step.

EXAMPLE H 3S and 3R-(hydroxyimino)-1-(S-α-methylbenzyl)pyrrolidin-5-one,6 and 7

To a solution of the ketone, 5 (12.9 g, 56.0 mmol) in pyridine (223 mL),was added hydroxylamine hydrochloride (4.27 g, 61.6 mmol). The reactionwas warmed to 45° C. After stirring for 24 hours, the pyridine wasremoved in vacuo, and the residue was dissolved in CHCl₃ (230 mL). TheCHCl₃ layer was extracted with 0.5N HCl (11×75.0 mL), dried with MgSO₄and concentrated to a solid (14.2 g). The crude product waschromatographed [silica gel/EtOAc] giving pure diastereomers;3S-3-(hydroxyimino)-1-(S-α-methylbenzyl)pyrrolidin-5-one, 6, (Rf=0.40,mp 109°-110° C., 5.36 g, 38.9%). Mixture of 6 and 7 (3.21 g, 23.3%) and3R-3-(hydroxyimino)-1-(S-α-methylbenzyl)pyrrolidin-5-one, 7, (Rf=0.31,mp 125°-127° C., 3.15 g, 22.8%) as solids.

6; ¹ H-NMR (CDCl₃) δ1.50 (d, J=7.0 Hz, 3H), 1.84 (s, 3H), 2.56-2.68 (m,2H), 2.93-3.22 (m, 2H), 3.34 (dd, J=9.6, 7.0 Hz, 1H), 5.51 (q, J=7.0 Hz,1H), 7.22-7.43 (m, 5H), 8.65 (s, 1H); Anal. [C₁₄ H₁₈ N₂ O₂ ]:

(Calc., found): C, (68.27, 68.11); H, (7.37, 7.33); N, (11.37, 11.26).

7; ¹ H-NMR (CDCl₃) δ1.53 (d, J=7.2 Hz, 3H), 1.70 (s, 3H), 2.49-2.70 (m,2H), 2.92 (dd, J=9.8, 6.4 Hz, 1H), 3.03-3.20 (m, 1H), 3.48 (dd, J=9.7,8.3 Hz, 1H), 5.53 (q, J=7.2 Hz, 1H), 7.19-7.40 (m, 5H), 8.12 (s, 1H);Anal. [C₁₄ H₁₈ N₂ O₂ ]

(Calc., found): C, (68.27, 68.11); H, (7.37, 7.65); N, (11.37, 11.19).

EXAMPLE I(3S,1'S)-3-(1'-aminoethlyl-1-(S-α-methylbenzyl)pyrrolidin-5-one, 10(3S,1'R)-3-(1'-aminoethyl-(S-α-methylbenzyl)pyrrolidin-5-one, 11

The oxime, 6, (11.5 g, 46.7 mmol) was dissolved in MeOH saturated withNH₃ (100 mL) and placed in a Parr shaker with Raney nickel (4.00 g). Thereaction was placed under 51.0 psi of hydrogen and shaken for 20 hours.The reaction was filtered and the filtrate was concentrated to an oil(11.4 g). The crude product was chromatographed [silica gel/CHCl₃:EtOH:TEA (20:1:1)] to give pure diastereomers;(3S,1'R)-3-(1'-aminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one, 11,(Rf=0.33, 3.02 g, 27.6%), a mixture of isomers-10 and 11 (1.73 g, 15.8%)and (3S,1'S)-3-(1'-aminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one, 10,(Rf=0.24, 5.70 g, 52.1%) as viscous oils.

11; ¹ H-NMR (CDCl₃) δ1.06 (d, J=6.4 Hz, 3H), 1.12 (br. s.,2H--disappears with D₂ O wash), 1.51 (d, J=7.2 Hz, 3H), 1.90-2.30 (m,2H), 2.46 (dd, J=16.2, 8.7 Hz, 1H), 2.72-2.92 (m, 1H), 3.12 (d, J=7.7Hz, 2H), 5.48 (q, J=7.2 Hz, 1H), 7.17-7.43 (m, 5H); IR (LF) 3359, 3030,1683, 1428, 701 cm⁻¹ ; Anal. [C₁₄ H₂₀ N₂ O, 0.10 H₂ O]

(Calc., found): C, (71.82, 71.84); H, (8.70, 8.64); N, (11.96, 12.16).

HPLC=99.5%.

10; ¹ H-NMR (CDCl₃ /200 MHz) δ0.99 (d, J=6.4 Hz, 3H), 1.18 (br. s.,2H--disappears with D₂ O wash), 1.49 (d, J=7.0 Hz, 3H), 2.00-2.37 (m,2H), 2.52 (dd, J=16.4, 9.0 Hz, 1H), 2.75-3.13 (m, 3H), 5.47 (q, J=7.0Hz, 1H), 7.13-7.42 (m, 5H); IR (LF) 3366, 2934, 1680, 1427, 701 cm⁻¹ ;Anal. [C₁₄ H₂₀ N₂ O, 0.09 H₂ O]:

(Calc., found): C, (71.88, 71.87); H, (8.69, 8.85); N, (11.97, 11.94).

HPLC=97.2%.

EXAMPLE J(3R,1'S)-3-(1'-aminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one, 8(3R,1'R)-3-(1'-aminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one, 9

In a manner similar to the reduction of 6 (Example I), the oxime 7 wasreduced and purified to give pure diastereomers;(3R,1'S)-3-(1'-aminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one, 8,(Rf=0.33, 3.96 g, 33.8%), a mixture of 8 and 9 (1.97 g, 16.7%) and(3R,1'R)-3-(1'-aminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one, 9,(Rf=0.24, 5.14 g, 43.8%) as viscous oils.

(3R,1'S)-3-(1'-aminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one, 9; ¹H-NMR (CDCl₃) δ1.03 (d, J=6.1 Hz, 3H), 1.21 (br. s., 2H--disappears withD₂ O wash), 1.52 (d, J=7.0 Hz, 3H), 2.00-2.30 (m, 2H), 2.38-2.60 (m,1H), 2.62-2.90 (m, 2H), 3.44 (dd, J=9.7, 7.7 Hz, 1H), 5.52 (q, J=7.0 Hz,1H), 7.17-7.50 (m, 5H); Anal. [C₁₄ H₂₀ N₂ O, 0.68 H₂ O]:

(Calc., found): C, (68.75, 68.77); H, (8.80, 8.68); N, (11.45, 11.30);[α]_(D) =-116° (c=1.0, CH₃ OH);

HPLC=99.1%.

(3R,1'R)-3-(1'-aminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one, 8; ¹ HNMR (CDCl₃) δ0.91 (d, J=6.3 Hz, 3H), 1.39 (br. s., 2H--disappears withD₂ O wash), 1.51 (d, J=7.3 Hz, 3H), 2.02-2.37 (m, 2H), 2.43-2.80 (m,3H), 3.25-3.43 (m, 1H), 5.51 (q, J=7.3 Hz, 1H), 7.17-7.43 (m, 5H); Anal.[C₁₄ H₂₀ N₂ O, 0.71 H₂ O]:

(Calc., found): C, (68.65, 68.29); H, (8.81, 8.38); N, (11.44, 11.23);[α]_(D) =-128° C. (c=1.0, CH₃ OH);

HPLC=99.4%.

EXAMPLE K (3S,1'R)-3-(1'-aminoethyl)-1-(S-α-methylbenzyl)pyrrolidine, 15

To dry THF (150 mL) cooled to 0° C. was added 95% LiAlH₄ (2.34 g, 58.6mmol) portionwise. The ice bath was removed and a solution of 11 (6.81g, 29.3 mmol) in dry THF (100 mL) was added dropwise. The reaction waswarmed to reflux. After 24 hours the reaction was cooled to roomtemperature and quenched by adding H₂ O (2.34 mL), then 15% NaOH (2.34mL), followed by H₂ O (7.20 mL). The reaction was filtered throughcelite and the pad was washed with THF. The filtrate was concentratedand the residue partitioned between CH₂ Cl₂ (50.0 mL) and H₂ O (15.0mL). The resulting phases were separated and the aqueous phase waswashed with CH₂ Cl₂ (3×10.0 mL). The CH₂ Cl₂ layers were combined, driedwith MgSO₄ and concentrated in vacuo to crude product (6.49 g). Thismaterial was distilled to give product as an oil (bp=89°-96° C. at 0.15mm, 5.56 g, 86.9%).

15; ¹ H-NMR (CDCl₃) δ1.04 (d, J=6.2 Hz, 3H), 1.31-1.73 (m, 6H--contains1.38 (d, J=6.6 Hz)), 1.77-2.11 (m, 2H), 2.13-2.27 (m, 1H), 2.38-2.57 (m,2H), 2.65-2.81 (m, 1H), 2.81-2.93 (m, 1H), 3.19 (q, J=6.6 Hz, 1H),7.16-7.43 (m, 5H); Anal. [C₁₄ H₂₂ N₂ ]:

(Calc., found): C, (77.01, 76.70); H, (10.16, 10.21); N, (12.83, 12.46).

EXAMPLE K-1 (3S,1'S)-3-(1'-aminoethyl)-1-(S-α-methylbenzyl)pyrrolidine,14

The reduction of 10 was carried out in the same manner as above to give14 (bp 91°-100° C. at 0.25 mm, 5.57 g, 79.9%).

¹ H-NMR (CDCl₃) δ1.00 (d, J=6.3 Hz, 3H), 1.24-1.47 (m, 5H--contains 1.37(d, J=6.6 Hz)), 1.49-1.67 (m, 1H), 1.80-2.16 (m, 3H), 2.38-2.59 (m, 2H),2.65-2.86 (m, 2H), 3.16 (q, J=6.6 Hz, 1H), 7.13-7.38 (m, 5H); Anal. [C₁₄H₂₂ N₂ ]:

(Calc., found): C, (77.01, 76.66); H, (10.16, 10.08); N, (12.83, 12.50).

EXAMPLE K-2 (3R,1'S)-3-(1'-aminoethyl)-1-(S-α-methylbenzyl)pyrrolidine,12

Compound 8 (3.44 g, 14.8 mmol) was reduced as in K and gave 12(bp=92°-101° C. at 0.10 mm, 2.53 g 78.0%); Anal. [C₁₄ H₂₂ N₂ ]:

(Calc., found): C, (77.01, 76.59); H, (10.16, 9.96); N, (12.83, 11.98).

EXAMPLE K-3 (3R,1'R)-3-(1'-aminoethyl)-1-(S-α-methylbenzyl)pyrrolidine,13

Compound 9 (4.51 g, 19.4 mmol) was reduced as in K and gave 13 (bp83°-94° C. at 0.05 mm, 2.93 g, 68.9%);

Anal. [C₁₄ H₂₂ N₂ ]: (Calc., found): C, (77.01, 76.21); H, (10.16,10.28); N, (12.83, 12.20).

General preparation of the3-(1'-N-t-butyloxycarbonylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidines(16-19)

The pyrrolidines (12-15) were added to a cold solution ofdi-t-butyloxycarbonate (1.10-1.20 eq), 1N NaOH (1.10-1.20 eq) and t-BuOH(35-50 mL). The ice bath was removed and the reactions stirred at roomtemperature. After stirring 24 hours, the product was isolated bydiluting the reaction with H₂ O (100 mL) and extracting the aqueoussolution with ether (5×25 mL). The ether layers were combined, driedwith MgSO₄ and concentrated in vacuo to give crude product. The crudeproducts were purified by chromatography [silica gel/CH₂ Cl₂:EtOH(90:10)/] to give pure products.

EXAMPLE L(3S,1'R)-3-N-t-butyloxycarbonylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine,19

This compound was obtained from 15 using the general procedure described(Rf=0.24, 4.87 g, 62.5%); ¹ H-NMR (CDCl₃) δ1.06 (d, J=6.6 Hz, 3H),1.30-1.68 (m, 13H--contains 1.38 (d, J=6.7 Hz) and 1.46 (s)), 1.83-2.23(m, 2H), 2.25-2.60 (m, 3H), 2.68-2.90 (m, 1H), 3.19 (q, J=6.5 Hz, 1H),3.40-3.63 (m, 1H), 5.26-5.47 (m, 1H), 7.17-7.43 (m, 5H); Anal. [C₁₉ H₃₀N₂ O, 0.13 CH₂ Cl₂ ]:

(Calc., found): C, (69.73, 69.68); H, (9.26, 9.17); N, (8.50, 8.50).

EXAMPLE L-1(3S,1'S)-3-(1'-N-t-butyloxycarbonylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine,18

This compound was obtained from 14 using the general procedure described(Rf=0.33, 5.18 g, 67.4%); ¹ H-NMR (CDCl₃) δ1.11 (d, J=6.2 Hz, 3H),1.30-2.00 (m, 14H--contains 1.37 (d, J=6.3 Hz)), 2.03-2.38 (m, 3H),2.43-2.63 (m, 1H), 2.65-2.85 (m, 1H), 3.14 (q, J=6.4 Hz, 1H), 3.37-3.63(m, 1H), 5.20 (br. s., 1H), 7.17-7.43 (m, 5H); Anal. [C₁₉ H₃₀ N₂ O₂,0.17 CH₂ Cl₂ ]:

(Calc., found): C, (69.17, 69.15); H, (9.19, 8.98); N, (8.41, 8.22).

EXAMPLE L-2(3R,1'S)-3-(1'-N-t-butyloxycarbonylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine,16

This compound was obtained from 12 using the general procedure described(Rf=0.24, 1.64 g, 44%); ¹ H-NMR (CDCl₃) δ1.16 (d, J=7.3 Hz, 3H),1.32-1.66 (m, 13H), 1.85-2.27 (m, 2H), 2.30-2.87 (m, 4H), 3.10-3.33 (m,1H), 3.40-3.67 (m, 1H), 5.65 (br. s., 1H), 7.17-7.43 (m, 5H); Anal. [C₁₉H₃₀ N₂ O₂, 0.19 CH₂ Cl₂ ]:

(Calc., found): C, (68.89, 68.96); H, (9.15, 8.86); N, (8.37, 8.13).

EXAMPLE L-3(3R,1'R)-3-(1'-N-t-butyloxycarbonylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine,17

This procedure was obtained from 13 using the general proceduredescribed (Rf=0.33, 1.76 g, 45.4%); ¹ H-NMR (CDCl₃) δ1.07 (d, J=7.3 Hz,3H), 1.32-1.55 (m, 12H), 1.55-1.77 (m, 1H), 1.77-2.03 (m, 1H), 2.03-2.87(m, 5H), 3.07-3.30 (m, 1H), 3.43-3.70 (m, 1H), 5.13 (br. s., 1H),7.17-7.43 (m, 5H); Anal. [C₁₉ H₃₀ N₂ O₂, 0.08 CH₂ Cl₂ ]:

(Calc., found): C, (70.46, 70.39); H, (9.35, 9.10); N, (8.61, 8.70).

General Procedure for the Preparation of3-(1'-N-t-butyloxycarbonylaminoethyl)pyrrolidines, 20-23

The compound (16-19) was dissolved in MeOH (100 mL) and 20% Pd/C(0.30-1.00 g) in a Parr shaker. The reaction was placed under H₂ (50.0psi). After shaking 18-26 hours, additional catalyst was required(0.30-1.60 g). The reaction was shaken for another 2-6 hours, thenfiltered. The filtrate was concentrated in vacuo and the residue wastaken up in H₂ O. The aqueous solution was extracted with diethyl ether,made basic with 50% NaOH, extracted with CH₂ Cl₂ or CHCl₃. The combinedorganic layers were dried with MgSO₄ and concentrated to a waxy solid.These compounds were used as is or were purified by trituration withether or ether/pentane and filtration of the purified solid.

EXAMPLE M (3S,1'R)-3-(1'-N-t-butyloxycarbonylaminoethyl)pyrrolidine, 23

Compound 23 was obtained from 19 using the method described above; (0.93g, 62.8%); ¹ H-NMR (CDCl₃) δ1.15 (d, J=6.5 Hz, 3H), 1.30-1.57 (m, 10H),1.72-2.15 (m, 2H), 2.60 (br. s., disappears with D₂ O wash), 2.70-2.86(m, 1H), 2.87-3.17 (m, 3H), 3.43-3.70 (m, 1H), 4.50-4.73 (m,1H--disappears with D₂ O wash); Anal. [C₁₁ H₂₂ N₂ O₂, 0.08 CH₂ Cl₂ ]:

(Calc., found): C, (60.19, 60.25); H, (10.10, 9.77); N, (12.67, 12.30).

EXAMPLE M-1 (3S,1'S)-3-(1'-N-t-butyloxycarbonylaminoethyl)pyrrolidine,22

Compound 22 was obtained from 18 using the method described above; (0.72g, 89.8%); ¹ H-NMR (CDCl₃) δ1.11 (d, J=6.5 Hz, 3H), 1.30-1.63 (m, 10H),1.73-2.15 (m, 2H), 2.43-2.67 (m, 1H), 2.77-3.12 (m, 3H), 3.45-3.70 (m,1H). Anal. [C₁₁ H₂₂ N₂ O₂ ]:

(Calc., found): C, (61.65, 60.82); H, (10.35, 10.10); N, (13.07, 12.03).

Used without further purification in the next step.

EXAMPLE M-2 (3R,1'S)-3-(1'-N-t-butyloxycarbonylaminoethyl)pyrrolidine,20

Compound 20 was obtained from 16 using the method described above; mp71.5°-74.5° C.; ¹ H-NMR (CDCl₃) δ1.15 (d, J=6.5 Hz, 3H), 1.30-1.60 (m,10H--contains 1.44 (s)), 1.70-2.13 (m, 2H--contains broad peak whichdisappears with D₂ O wash), 2.66-3.10 (m, 4H), 3.42-3.70 (m, 1H), 4.62(br. s., 1H--disappears with D₂ O wash); Anal. [C₁₁ H₂₂ N₂ O₂, 0.25 H₂O]:

(Calc., found): C, (60.38, 60.37); H, (10.36, 10.09); N, (12.80, 12.62).

EXAMPLE M-3 (3R,1'R)-3-(1'-N-t-butyloxycarbonylaminoethyl)pyrrolidine,21

Compound 21 was obtained from 17 using the method described above; mp85.5°-88.5° C.; ¹ H-NMR (CDCl₃) δ1.12 (d, J=6.5 Hz, 3H), 1.21-1.67 (m,10H--contains 1.44 (s)), 1.73-2.17 (m, 2H--contains br. s. whichdisappears with D₂ O wash), 2.50-2.68 (m, 1H), 2.80-3.17 (m, 3H),3.43-3.75 (m, 1H), 4.50 (br. s., 1H--disappears with D₂ O wash); Anal.[C₁₁ H₂₂ N₂ O₂, 0.25 H₂ O]:

(Calc., found): C, (60.38, 60.36); H, (10.36, 10.16); N, (12.80, 12.63).

General Procedure for the Preparation of the3-(1'-N,N-dimethylaminoethyl)-1-S-α-methylbenzyl)pyrrolidinones 24-27

To the chiral amines (8-11), cooled in an ice/water bath was added 88%formic acid (2.5 eq) and 35% formaldehyde. The ice bath was removed andthe reaction was warmed slowly over 25-60 minutes. Gas evolutionoccurred. The reaction was then warmed to reflux for five hours, cooledto room temperature, and made basic with 1N NaOH. The reaction wasextracted with diethyl ether. The combined ether layers were washed withsaturated NaCl, dried with MgSO₄, filtered and concentrated in vacuo toprovide the desired products.

EXAMPLE N(3S,1'R)-3-(1'-N,N-dimethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one,27

The compound 27 was obtained from 11 as described above; bp 0.20-0.25mm, mp 140°-157° C.; ¹ H-NMR (CDCl₃) δ0.88 (d, J=6.5 Hz, 3H), 1.52 (d,J=7.1 Hz, 3H), 2.03-2.32 (m, 8H--contains 2.14 (s)), 2.35-3.55 (m, 2H),3.01-3.30 (m, 2H), 5.48 (q, J=7.1 Hz, 1H), 7.19-7.40 (m, 5H); Anal. [C₁₆H₂₄ N₂ O]:

(Calc., found): C, (73.81, 73.48); H, (9.29, 9.47); N, (10.76, 10.55).

EXAMPLE N-1(3S,1'S)-3-(1'-N,N-dimethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one,26

The compound 26 was obtained from 10 as described above. The crudeproduct was recrystallized from diethyl ether to give (1.31 g, 30%). Thefiltrate was concentrated to give an additional material which was usedwithout further purification (2.52 g, 57.6%); ¹ H-NMR (CDCl₃) δ0.83 (d,J=6.4 Hz, 3H), 1.51 (d, J=7.1 Hz, 3H), 2.08-2.59 (m, 10H--contains 2.18(s)), 2.87-3.07 (m, 2H), 5.50 (q, J=7.1 Hz, 1H), 7.19-7.40 (m, 5H);Anal. [C₁₆ H₂₄ N₂ O]:

(Calc., found): C, (73.81, 73.68); H, (9.29, 9.46); N, (10.76, 10.71).

EXAMPLE N-2(3R,1'S)-3-(1'-N,N-dimethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one,24

The compound 24 was obtained from 8 as described above; (12.54 g,92.3%); ¹ H-NMR (CDCl₃) δ0.84 (d, J=6.0 Hz, 3H), 1.52 (d, J=7.1 Hz, 3H),1.97-2.20 (m, 7H--contains 2.11 (s)), 2.20-2.58 (m, 3H), 2.88 (dd,J=10.1, 6.8 Hz, 1H), 3.38 (dd, J=10.1, 7.3 Hz, 1H), 5.51 (q, J=7.1 Hz,1H), 7.18-7.43 (m, 5H); Anal. [C₁₆ H₂₄ N₂ O, 0.15 H₂ O]:

(Calc., found): C, (73.05, 73.37); H, (9.31, 9.38); N, (10.65, 10.25).

EXAMPLE N-3(3R,1'R)-3-(1'-N,N-dimethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one,25

The desired product 25 was obtained from 9 as described above; (11.27 g,83.8%); ¹ H-NMR (CDCl₃) δ0.73 (d, J=5.9 Hz, 3H), 1.52 (d, J=7.1 Hz, 3H),2.15 (s, 6H), 2.22-2.63 (m, 5H), 3.22-3.38 (m, 1H), 5.52 (q, J=7.1 Hz,1H), 7.18-7.43 (m, 5H); Anal. [C₁₆ H₂₄ N₂ O, 0.17 H₂ O]:

(Calc., found): C, (72.95, 73.00); H, (9.31, 9.69); N, (10.63, 10.39).

General Procedure for the Preparation of the3-(1'-N,N-dimethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidines 28-31

To cold, dry THF (100-200 mL) was added 95% LiAlH₄ (2 eq). The ice bathwas removed and a solution of the chiral amides (24-27) in THF (50 mL)was added dropwise. The reaction was refluxed 17-18 hours then cooled toroom temperature. The reaction was quenched by adding first 1 mL of H₂O/gram of LiAlH₄ used followed by 1 mL of 15% NaOH/gram of LiAlH₄ usedand finally 3 mL of H₂ O/gram of LiAlH₄ used. The suspension wasfiltered through celite and the filter pad was washed with THF. Thefiltrate was concentrated and the residue was partitioned between CH₂Cl₂ and saturated NaCl solution. The resulting layers were isolated. Theaqueous layer was washed with CH₂ Cl₂. The CH₂ Cl₂ layers were combined,dried with MgSO₄ and concentrated in vacuo. The crude material wasdistilled to give the pure product.

EXAMPLE O(3S,1'R)-3-(1'-N,N-dimethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine,31

Compound 31 (4.65 g, 80%) was obtained from 27 as described; bp0.10-0.15 mm Hg, 95°-105° C.; ¹ H-NMR (CDCl₃) δ0.86 (d, J=6.2 Hz, 3H),1.23-1.46 (m, 4H--contains 1.39 (d, J=6.6 Hz)), 1.74-1.95 (m, 1H),2.08-2.46 (m, 10H), 2.46-2.61 (m, 1H), 3.00-3.24 (m, 2H--contains 3.18(q, J=6.6 Hz)), 7.11-7.38 (m, 5H); Anal. [C₁₆ H₂₆ N₂ ]:

(Calc., found): C, (77.99, 77.70); H, (10.64, 10.98); N, (11.37, 11.32).

EXAMPLE O-1(3S,1'S)-3-(1'-N,N-dimethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine,30

Compound 30 (3.97 g, 79%) was obtained from 26 as described; bp 0.15 mmHg, 96°-102° C.; ¹ H-NMR (CDCl₃) δ0.83 (d, J=6.4 Hz, 3H), 1.38 (d, J=6.6Hz, 3H), 1.54-1.78 (m, 1H), 1.78-2.04 (m, 2H), 2.07-2.41 (m,9H--contains 2.19 (s)), 2.41-2.62 (m, 1H), 2.90 (dd, J=8.5, 7.7 Hz, 1H),3.17 (q, J=6.6 Hz, 1H), 7.12-7.36 (m, 5H); Anal. [C₁₆ H₂₆ N₂ ]:

(Calc., found): C, (77.99, 77.52); H, (10.64, 11.02); N, (11.37, 11.06).

EXAMPLE O-2(3R,1'S)-3-(1'-N,N-dimethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine,28

Compound 28 (9.06 g, 82%) was obtained from 24 as described; bp 0.10 mmHg, 98°-109° C.; ¹ H-NMR (CDCl₃, 250 MHz) 0.85 (d, J=6.4 Hz, 3H),1.24-1.45 (m, 4H--contains 1.36 (d, J=6.6 Hz), 1.77-2.00 (m, 1H),2.00-2.48 (m, 10H--contains 2.14 (s)), 2.61-2.83 (m, 2H), 3.19 (q, J=6.6Hz, 1H), 7.12-7.37 (m, 5H); Anal. [C₁₆ H₂₆ N₂ ]:

(Calc., found): C, (77.99, 77.96); H, (10.64, 10.72); N, (11.34, 11.36).

EXAMPLE O-3(3R,1'R)-3-(1'-N,N-dimethylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine,29

Compound 29 (7.99 g, 80%) was obtained from 25 as described; bp 0.10 mmHg, 103°-109° C.; ¹ H-NMR (CDCl₃) δ0.75 (d, J=6.4 Hz, 3H), 1.37 (d,J=6.6 Hz, 3H), 1.58-1.77 (m, 1H), 1.81-2.46 (m, 11H--contains 2.17 (s)),2.51-2.66 (m, 1H), 2.85-3.00 (m, 1H), 3.15 (q, J=6.6 Hz, 1H), 7.15-7.38(m, 5H). Anal. [C₁₆ H₂₆ N₂ ]:

(Calc., found): C, (77.99, 77.95); H, (10.64, 10.75); N, (11.36, 11.23).

General Procedure for the Preparation of3-(1'-N,N-dimethylaminoethyl)pyrrolidines 32-35

The chiral amines (28-31) were dissolved in MeOH (100 mL) and placed ina Parr shaker. To this solution was added 20% Pd/C (1.00-1.50 g). Thereaction was placed under H₂ gas (50 psi) and shaken for 3-4 hours. Thereaction was filtered and the filtrate was concentrated in vacuo. Theresidue was distilled to give pure product.

EXAMPLE P (3S,1'R)-3-(1'-N,N-dimethylaminoethyl)pyrrolidine, 35

Compound 35 (1.76 g, 56%) was obtained from 31 as described; bp 10.0 mmHg, 89°-104° C.); ¹ H-NMR (CDCl₃) δ0.91 (d, J=6.4 Hz, 3H), 1.19-1.40 (m,1H), 1.75-2.12 (m, 3H), 2.20 (s, 6H), 2.25-2.47 (m, 1H), 2.69 (dd,J=10.9, 8.1 Hz, 1H), 2.82-3.02 (m, 2H), 3.10 (dd, J=10.9, 7.6 Hz, 1H);¹³ C-NMR (CDCl₃, 250 MHz) 9.5, 30.8, 40.2, 44.2, 47.0, 51.7, 63.2; Anal.[C₈ H₁₈ N₂, 0.10 H₂ O]:

(Calc., found): C, (66.71, 66.95); H, (12.74, 12.64); N, (19.45, 19.09).

EXAMPLE P-1 (3S,1'S)-3-(1'-N,N-dimethylaminoethyl)pyrrolidine, 34

Compound 34 (1.19 g, 71%) was obtained from 30 as described; bp 10.0 mmHg, 83°-110° C.; ¹ H-NMR (CDCl₃) δ0.87 (d, J=6.4 Hz, 3H), 1.47-1.67 (m,1H), 1.82-2.13 (m, 2H), 2.22 (s, 6H), 2.28-2.53 (m, 2H), 2.82-2.98 (m,2H).

EXAMPLE P-2 (3R,1'S)-3-(1'-N,N-dimethylaminoethyl)pyrrolidine, 32

Compound 32 (3.53 g, 68%) was obtained from 28 as described; bp 14.0 mmHg, 81°-84° C.; ¹ H-NMR (CDCl₃), δ0.90 (d, J=6.1 Hz, 3H), 1.17-1.41 (m,1H), 1.73-2.13 (m, 2H), 2.20 (s, 6H), 2.25-2.47 (m, 1H), 2.68 (dd,J=11.0, 7.9 Hz, 1H), 2.81-3.00 (m, 2H), 3.08 (dd, J=11 Hz, 7.3 Hz, 1H);¹³ C NMR (CDCl₃, 63 MHz), 9.3, 30.7, 40.1, 44.1, 46.9, 51.6, 63.1; Anal.[C₈ H₁₈ N₂, 0.12H₂ O] (Calc. found): C (66.54, 66.41); H (12.73, 12.79);N (19.40, 19.79).

EXAMPLE P-3 (3R,1'R)-3-(1'-N,N-dimethylaminoethyl)pyrrolidine, 33

Compound 33 (3.04 g, 68%) was obtained from 29 as described; bp15.0-17.0 mm Hg, 83°-86° C.; ¹ H-NMR (CDCl₃ +D₂ O) δ0.87 (d, J=6.3 Hz,3H), 1.44-1.68 (m, 1H), 1.97-2.52 (m, 10H--contains 2.22 (s)), 2.78-3.11(m, 3H--contains 3.01 (dd, J=10.5, 7.5 Hz)). Anal. [C₈ H₁₈ N₂, 0.09 H₂O] (Calc., found): C (66.79, 66.78); H (12.74, 13.00); N (19.47, 19.74).

General Procedure for the Preparation of the3-(1'-N-tert-butoxycarbonylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-ones,48-50

A solution of di-tert-butylcarbonate (1.1 eq) in dichloromethane wasadded portionwise to a stirred solution of the corresponding primaryamine (8-11) and triethylamine (1.1 eq) in dichloromethane (250 mL). Theresulting solution was stirred at room temperature for 20 hours, andthen concentrated under reduced pressure to give a light yellow oil.These crude products were purified by column chromatography (silica gel,heptane-isopropanol 4:1).

EXAMPLE Q(3R,1'R)-3-(1'-N-tert-butoxycarbonylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one,49

From 6.68 g (28.7 mmol) of amine 9, 7.64 g (35 mmol) ofdi-tert-butylcarbonate, and 3.54 g (35 mmol) of triethylamine, there wasobtained 49 (5.43 g, 57%) as a white, wax-like glass.

[α]_(D) =-116° (c=0.99, chloroform).

¹ H-NMR (CDCl₃) δ0.96 (d, 3H, J=6.7 Hz), 1.38 (s, 9H), 1.52 (d, 3H,J=7.2 Hz), 2.23-2.55 (m, 3H), 2.66 (dd, 1H, J=9.8, 7.0 Hz), 3.32 (dd,1H, J=9.8, 8.1 Hz), 3.50-3.70 (m, 1H), 4.35-4.45 (m, 1H), 5.50 (q, 1H,J=7.1 Hz), 7.23-7.37 (m, 5H).

Anal. Calcd. for C₁₉ H₂₈ N₂ O₃ : C, 68.65; H, 8.49; N, 8.43 Found: C,68.55; H, 8.53; N, 8.13.

EXAMPLE Q-1(3R,1'S)-3-(1'-N-tert-butoxycarbonylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one,48

From 5.95 g (25.6 mmol) of amine 8, 6.77 g (31.0 mmol) ofdi-tert-butylcarbonate, and 3.14 g (31.0 mmol) of triethylamine, therewas obtained 48 (7.46 g, 88%) as a white, wax-like glass.

[α]_(D) =-127° (c=1.04, chloroform).

¹ H-NMR (d₆ -DMSO) δ0.90 (d, 3H, J=6.5 Hz), 1.34 (s, 9H), 1.44 (d, 3H,J=7.1 Hz), 2.04-2.20 (m, 1H), 2.21-2.41 (m, 2H), 2.69 (dd, 1H, J=9.6,6.5 Hz), 3.28-3.42 (m, 2H), 5.25 (q, 1H, J=7.1 Hz), 6.78 and 6.85 (2×d,1H, J=8.6 and 7.9 Hz), 7.24-7.37 (m, 5H).

Anal. Calcd. for C₁₉ H₂₈ N₂ O₃ : C, 68.65; H, 8.49; N, 8.43. Found: C,68.45; H, 8.59; N, 8.38.

EXAMPLE Q-2(3S,1'R)-3-(1'-N-tert-butoxycarbonylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one,51

From 10.19 g (44 mmol) of amine 11, 11.57 g (53 mmol) ofdi-tert-butylcarbonate, and 5.36 g (53 mmol) of triethylamine, there wasobtained 51 (13.16 g, 90%) as a white solid; mp 120°-121° C. (fromdichloromethane-heptane).

[α]_(D) =-32° (c=0.96, chloroform).

¹ H-NMR (CDCl₃) δ1.10 (d, 3H, J=6.6 Hz), 1.41 (s, 9H), 1.50 (d, 3H,J=7.2 Hz), 2.14-2.29 (m, 2H), 2.45 (dd, 1H, J=19.5, 12.2 Hz), 2.99-3.06(m, 1H), 3.12-3.19 (m, 1H), 3.57-3.68 (m, 1H), 4.81 (br. d, 1H, J=9.1Hz), 5.45 (q, 1H, J=7.1 Hz), 7.19-7.35 (m, 5H).

Anal. Calcd. for C₁₉ H₂₈ N₂ O₃ : C, 68.65; H, 8.49; N, 8.43. Found: C,68.66; H, 8.64; N, 8.38.

EXAMPLE Q-3(3S,1'S)-3-(1'-N-tert-butoxycarbonylaminoethyl)-1-(S-α-methyl-benzyl)pyrrolidin-5-one,50

From 10.02 g (43 mmol) of amine 10, 11.35 g (52 mmol) ofdi-tert-butylcarbonate, and 5.26 g (52 mmol) of triethylamine, there wasobtained 50 (13.00 g, 91%) as a white solid; mp 148°-149° C. (fromdichloromethane-hexane).

[α]_(D) =-110° (c=1.03, chloroform).

¹ H-NMR (CDCl₃) δ1.08 (d, 3H, J=6.7 Hz), 1.43 (s, 9H), 1.50 (d, 3H,J=7.1 Hz), 2.20-2.56 (m, 3H), 2.97-3.13 (m, 2H), 3.70-3.83 (m, 1H), 4.76(br. d, 1H, J=9.1 Hz), 5.48 (q, 1H, J=7.1 Hz), 7.23-7.36 (m, 5H).

Anal. Calcd. for C₁₉ H₂₈ N₂ O₃ : C, 68.64; H, 8.49; N, 8.43. Found: C,68.50; H, 8.61; N, 8.57.

General Procedure for the Preparation of the3-(1'-N-methylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidines, 52-55

A solution of3-(1'-N-tert-butoxycarbonylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidin-5-one(48-51) in dry THF (25 mL) was added dropwise to a stirred suspension oflithium aluminum hydride (2 equivalents) in dry THF (10 mL). Thesuspension was heated at reflux for six hours, allowed to cool to roomtemperature, and quenched by the dropwise addition of saturated aqueousammonium sulfate solution (2 mL) and water (2 mL). The resulting slurrywas stirred at room temperature for a few minutes and then filteredthrough a pad of Celite. The solids were rinsed with dichloromethane,and the combined filtrate and washings were dried and concentrated toafford the corresponding3-(1'-N-methylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine.

EXAMPLE R(3R,1'R)-3-(1'-N-methylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine, 53

From 11.80 g (36 mmol) of 49 and 2.69 g (71 mmol) of LiAlH₄, the aboveprocedure provided 53 (7.85 g, 94%) as a yellow oil.

[α]_(D) =-75° (c=1.90, chloroform).

¹ H-NMR (CDCl₃) δ0.94 (d, 3H, J=6.3 Hz), 1.12-1.40 (m, 1H), 1.36 (d, 3H,J=6.4 Hz), 1.50-1.63 (m, 1H), 1.88-2.07 (m, 1H), 2.09-2.20 (m, 2H),2.25-2.45 (m, 2H), 2.39 (s, 3H), 2.49-2.62 (m, 1H), 2.72-2.81 (m, 1H),3.15 (q, 1H, J=6.5 Hz), 7.21-7.33 (m, 5H).

Anal. Calcd. for C₁₅ H₂₄ N₂.0.25H₂ O: C, 76.06; H, 10.43; N, 11.83.Found: C, 76.20; H, 10.16; N, 11.57.

EXAMPLE R-1(3R,1'S)-3-(1'-N-methylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine, 52

From 5.30 g (16 mmol) of 48 and 1.21 g (32 mmol) of LiAlH₄ the aboveprocedure provided 52 (3.54 g, 95%) as a clear liquid.

¹ H-NMR (CDCl₃) δ1.01 (d, 3H, J=6.2 Hz), 1.36 (d, 3H, J=6.5 Hz),1.40-1.55 (m, 1H), 1.83-2.02 (m, 1H), 2.04-2.20 (m, 2H), 2.27-2.44 (m,2H), 2.35 (s, 3H), 2.63-2.69 (m, 1H), 2.74-2.85 (m, 1H), 3.16 (q, 1H,J=6.6 Hz), 7.20-7.34 (m, 5H).

Anal. Calcd. for C₁₅ H₂₄ N₂.0.04 CH₂ Cl₂ : C, 76.62; H, 10.29; N, 11.88Found: C, 76.55; H, 10.69; N, 11.57.

EXAMPLE R-2(3S,1'R)-3-(1'-N-methylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine, 55

From 14.95 g (45 mmol) of 51 and 3.42 g (90 mmol) of LiAlH₄, the aboveprocedure provided 55 (9.12 g, 87%) as a light yellow oil.

[α]_(D) =-49° (c=0.89, chloroform).

¹ H-NMR (CDCl₃) δ1.02 (d, 3H, J=6.2 Hz), 1.38 (d, 3H, J=6.6 Hz),1.43-1.54 (m, 1H), 1.78-1.92 (m, 1H), 2.09-2.29 (m, 2H), 2.35-2.40 (m,1H), 2.38 (s, 3H), 2.46 (t, 2H, J=6.9 Hz), 2.83-2.93 (m, 1H), 3.19 (q,1H, J=6.6 Hz), 7.20-7.34 (m, 5H).

Anal. Calcd. for C₁₅ H₂₄ N₂.0.25 H₂ O: C, 76.06; H, 10.43; N, 11.83Found: C, 76.10; H, 10.54; N, 12.04.

EXAMPLE R-3(3S,1'S)-3-(1'-N-methylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine, 54

From 12.74 g (38 mmol) of 50 and 2.66 g (70 mmol) of LiAlH₄, the aboveprocedure provided 54 (7.30 g, 82%) as a faint yellow oil.

[α]_(D) =-38° (c=1.00, chloroform).

¹ H-NMR (CDCl₃) δ0.98 (d, 3H, J=6.2 Hz), 1.37 (d, 3H, J=6.6 Hz),1.47-1.70 (m, 2H), 1.81-1.95 (m, 1H), 2.08-2.23 (m, 2H), 2.30-2.58 (m,3H), 2.39 (s, 3H), 2.65-2.78 (m, 1H), 3.16 (q, 1H, J=6.6 Hz), 7.21-7.37(m, 5H).

Anal. Calcd. for C₁₅ H₂₄ N₂.0.50 H₂ O: C, 74.64; H, 10.44; N, 11.61Found: C, 74.82; H, 10.29; N, 11.48.

General Procedure for the Preparation of the3-(1'-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidines,56-59

A solution of di-tert-butylcarbonate (1.1-1.3 eq) in dichloromethane (5mL) was added portionwise to a chilled solution of3-(1'-N-methylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidines (52-55) andtriethylamine (1.1-1.3 eq) in dichloromethane (15 mL). The resultingsolution was stirred at room temperature overnight, and thenconcentrated to afford the product as a viscous yellow oil. The crudeproduct was purified by column chromatography (silica gel,hexanes/2-propanol 4:1).

EXAMPLE S(3R,1'R)-3-(1'-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine,57

From 3.33 g (14 mmol) of amine 53, 3.71 g (17 mmol) ofdi-tert-butylcarbonate, and 1.72 g (17 mmol) of triethylamine, the aboveprocedure provided 57 (4.17 g, 88%) as a yellow oil which solidifiedupon cooling to 0° C.

[α]_(D) =-25° (c=0.25, chloroform).

¹ H-NMR (CDCl₃) δ0.92 and 0.95 (2×d superimposed, 3H), 1.36 d, 3H, J=6.5Hz), 1.40-1.60 (m, 1H), 1.46 (s, 9H), 1.75-1.93 (m, 2H), 2.08-2.35 (m,2H), 2.55-2.71 (m, 4H), 2.90-3.09 (m, 1H), 3.11-3.24 (m, 1H), 3.75-3.90and 3.98-4.12 (m, 1H), 7.18-7.37 (m, 5H).

Anal. Calcd. for C₂₀ H₃₂ N₂ O₂.0.03 CH₂ Cl₂.0.72 C₄ H₈ O₂ : C, 69.06; H,9.57; N, 7.03 Found: C, 69.04; H, 9.59; N, 7.05.

EXAMPLE S-1(3R,1'S)-3-(1'-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine,56

From 3.45 g (15 mmol) of amine 52, 3.93 g (18 mmol) ofdi-tert-butylcarbonate, and 1.82 g (18 mmol) of triethylamine, the aboveprocedure provided 56 (3.92 g, 80%) as an oil.

[α]_(D) =-71° (c=0.65, chloroform).

¹ H-NMR (CDCl₃) δ1.05 (d, 3H, J=6.7 Hz), 1.30-1.45 (m, 12H), 1.85-2.09(m, 2H), 2.10-2.28 (m, 1H), 2.30-2.50 (m, 2H), 2.54 and 2.64 (2×s, 3H),2.65-2.85 and 2.89-3.06 (2×m, 1H), 3.16 (q, 1H, J=6.6 Hz), 3.75-3.91 and3.98-4.13 (2×m, 1H), 7.15-7.35 (m, 5H).

Anal. Calcd. for C₂₀ H₃₂ N₂ O₂.0.1 H₂ O: C, 71.86; H, 9.71; N, 8.38Found: C, 72.23; H, 10.11; N, 8.21.

EXAMPLE S-2(3S,1'R)-3-(1'-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine,59

From 9.00 g (38.7 mmol) of amine 55, 10.15 g (46.5 mmol) ofdi-tert-butylcarbonate, and 4.71 g (46.5 mmol) of triethylamine, theabove procedure provided 59 (10.86 g, 84%) as an oil.

[α]_(D) =-28° (c=0.99, chloroform).

¹ H-NMR (d₆ -DMSO, 75° C.) δ1.03 (d, 3H, J=6.7 Hz), 1.28 (d, 3H, J=6.7Hz), 1.33-1.42 (m, 10H), 1.78-1.88 (m, 1H), 2.14-2.28 (m, 2H), 2.40 (dd,1H, J=16.2, 7.3 Hz), 2.50 (t, 1H, J=7.8 Hz), 2.54-2.64 (m, 4H), 3.24 (q,1H, J=6.6 Hz), 3.75-3.93 (m, 1H), 7.20-7.31 (m, 5H).

Anal. Calcd. for C₂₀ H₃₂ N₂ O₂.0.1 H₂ O: C, 71.86; H, 9.71; N, 8.38Found: C, 71.80; H, 9.89; N, 8.44

EXAMPLE S-3(3S,1'S)-3-(1'-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-(S-α-methylbenzyl)pyrrolidine,58

From 7.13 g (31 mmol) of amine 54, 8.08 g (37 mmol) ofdi-tert-butylcarbonate, and 3.74 g (37 mmol) of triethylamine, the aboveprocedure provided 58 (9.15 g, 90%) as an oil.

[α]_(D) =-26° (c=1.00, chloroform).

¹ H-NMR (CDCl₃) δ1.03 and 1.20 (2×d, 3H, J=6.7 and 6.1 Hz), 1.38 (d, 3H,J=6.4 Hz), 1.39-1.50 (m, 1H), 1.45 (s, 9H), 1.63-1.80 (m, 1H), 1.90-2.01(m, 1H), 2.15-2.37 (m, 2H), 2.42-2.55 (m, 1H), 2.65 and 2.70. (2×s, 3H),2.84-2.99 (m, 1H), 3.10-3.21 (m, 1H), 3.72-4.11 (m, 1H), 7.16-7.34 (m,5H).

Anal. Calcd. for C₂₀ H₃₂ N₂ O₂.0.30 H₂ O: C, 71.09; H, 9.72; N, 8.29Found: C, 71.11; H, 9.88; N, 8.45.

General Procedure for the Preparation of the3-(1'-N-tert-butoxycarbonyl-N-methylaminoethyl)pyrrolidines, 60-63

A suspension of compound 56-59 (3 mmol) and 20% palladium-on-charcoalcatalyst (0.1 g) in methanol (10 mL) was placed in a Parr shaker andhydrogenated (50 psi) until no more uptake of hydrogen was observed andthin-layer-chromatography (dichloromethane-methanol 10:1) indicatedcomplete conversion. The suspension was filtered through a pad of Celiteand the filtrate concentrated to give the product.

EXAMPLE T(3R,1'S)-3-(1'-N-tert-butoxycarbonyl-N-methylaminoethyl)pyrrolidine, 60

From 3.35 g (10 mmol) of 56, there was obtained 60 (2.20 g, 96%) as apale yellow oil.

[α]_(D) =-2° (c=1.38, chloroform).

¹ H-NMR (250 MHz, CDCl₃): 1.13 (d, 3H, J=6.7 Hz), 1.30-1.48 (m, 1H),1.46 (s, 9H), 1.83-1.98 (m, 1H), 2.06-2.27 (m, 1H), 2.55-2.80 (m, 4H),2.83-3.25 (m, 4H), 3.73-3.92 and 3.97-4.12 (2×m, 1H).

Anal. Calcd. for C₁₂ H₂₄ N₂ O₂.0.45 H₂ O: C, 60.96; H, 10.61; N, 11.85Found: C, 61.27; H, 10.58; N, 11.43.

EXAMPLE T-1(3R,1'R)-3-(1'-N-tert-butoxycarbonyl-N-methylaminoethyl)pyrrolidine, 61

From 3.19 g (9.6 mmol) of 57, there was obtained 61 (2.16 g, 99%) as afaint yellow oil which solidified upon cooling to 0° C.

[α]_(D) =+15° (c=0.38, chloroform).

¹ H-NMR (CDCl₃) δ1.09 (d, 3H, J=6.7 Hz), 1.40-1.48 (m, 1H), 1.46 (s,9H), 1.70-1.84 (m, 1H), 2.12-2.27 (m, 1H), 2.47-2.62 (m, 1H), 2.70 and2.73 (2×s, 3H), 2.90-3.03 (m, 2H), 3.10 (dd, 1H, J=10.8, 7.7 Hz),3.78-3.90 and 3.98-4.10 (2×m, 2H).

Anal. Calcd. for C₁₂ H₂₄ N₂ O₂ : C, 63.12; H, 10.59; N, 12.27 Found: C,63.06; H, 10.59; N, 12.26.

EXAMPLE T-2(3S,1'R)-3-(1'-N-tert-butoxycarbonyl-N-methylaminoethyl)pyrrolidine, 63

From 10.12 g (30 mmol) of 59, there was obtained 63 (4.47 g, 64%) as aclear, colorless liquid; bp 100-°105° C. 1 mm Hg.

[α]_(D) =-1° (c=0.95, chloroform).

¹ H-NMR (CDCl₃) δ1.12 (d, 3H, J=6.7 Hz), 1.28-1.52 (m, 10H), 1.80-1.98(m, 1H), 2.05-2.23 (m, 1H), 2.51-2.79 (m, 4H), 2.80-3.08 (m, 3H),3.73-3.87 and 3.96-4.08 (2×m, 1H).

Anal. Calcd. for C₁₂ H₂₄ N₂ O₂.0.30 H₂ O: C, 61.66; H, 10.61; N, 11.98Found: C, 61.62; H, 10.56; N, 12.10.

EXAMPLE T-3(3S,1'S)-3-(1'-N-tert-butoxycarbonyl-N-methylaminoethyl)pyrrolidine, 62

From 8.16 g (25 mmol) of 58, there was obtained 62 (4.26 g, 76%) as acolorless oily liquid after vacuum distillation (bp 100°-102° C., ca. 1mm Hg). This product crystallized into a white, wax-like solid uponcooling to 0° C.

[α]_(D) =-12° (c=0.49, chloroform).

¹ H-NMR (CDCl₃) δ1.08 (d, 3H, J=6.7 Hz), 1.40-1.54 (m, 10H), 1.71-1.82(m, 1H), 2.06-2.20 (m, 1H), 2.47-2.58 (m, 2H), 2.69 and 2.73 (2×s, 3H),2.86-3.08 (m, 3H), 3.77-3.86 and 3.98-4.15 (2×m, 1H).

Anal. Calcd. for C₁₂ H₂₄ N₂ O₂.0.17 H₂ O: C, 62.29; H, 10.60; N, 12.11Found: C, 62.30; H, 10.74; N, 11.93.

PREPARATION OF FINAL PRODUCTS General Method for Coupling Pyrrolidinesto the Appropriate Quinolone Nucleus and Removal of the BOC Group

To the substrate (1.40-3.30 mmol) in CH₃ CN (10-30 mL) was addedtriethylamine (1.10-1.40 eq) and the diastereomerically pure pyrrolidine(1.10-1.20 eq). The reaction was stirred at room temperature (0-96hours) then warmed to reflux (6.5-48 hours). The reaction was cooled toroom temperature, stirred (0-18 hours) and filtered. The filter pad waswashed with CH₃ CN and/or ether, then air dried to give pure products assolids.

The amines were deprotected by one of three methods.

Method A: The protected quinolone (2.00-3.00 mmol) was dissolved in TFA(15.0 mL). After stirring one hour at 25° C., the reaction wasconcentrated in vacuo. The residue was dissolved in a minimum amount ofH₂ O. Fifty percent NaOH was added to make the pH of the solution equalto 12. The homogenous solution was filtered and the filtrate wasacidified with 3N HCl until the pH of the solution was equal to 8.3. Thefiltrate was filtered and the pad washed with a small amount of H₂ Oand/or 0.50N HCl. After drying, the solid was dissolved in concentratedHCl (14.0-40.0 mL). The acidic solution was centrifuged (little or nosolid present) and the supernatant was concentrated to dryness.

Method B: The protected quinolone (1.80-3.50 mmol) was suspended inabsolute EtOH (10.0-20.0 mL) and 1N HCl (5.00-10.0 mL). The reaction waswarmed to reflux and became homogeneous after a short period of time.After refluxing 2-5 hours, the reaction was allowed to cool to roomtemperature. After 3-18 hours, any solid formed was obtained byfiltration. The pad was washed sequentially with H₂ O and/or EtOH or IPAthen ether. After drying, pure product was obtained. Additional purematerial could be obtained from the filtrate. If, after stirring at roomtemperature, no solid had formed, the reaction was concentrated invacuo. The residue was triturated with IPA and the solid which formedwas filtered, washed with isopropanol and then ether to provide thedesired product.

Method C: Hydrogen chloride gas was bubbled during 3-5 minutes through asolution of the N-Boc protected compound (2.5 mmol) in dichloromethane(40 mL). A small amount of methanol was added to the reaction mixture todissolve the material that precipitated out, and the resulting solutionwas stirred at room temperature for 15-20 hours. The solvent wasevaporated and the residue was dissolved in hot methanol andcrystallized by the addition of ether. The solid was filtered, washedwith ether, and dried to provide the desired product.

EXAMPLE 13S,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-t-butyloxycarbonylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

The desired product (1.40 g, 92%) was obtained starting from pyrrolidine23 and quinolone B; mp 244.5°-245° C.; ¹ H-NMR (DMSO-d₆) δ1.03-1.35 (m,7H), 1.40 (s, 9H), 1.58-1.87 (m, 1H), 1.96-2.18 (m, 1H), 2.20-2.45 (m,1H), 3.37-3.83 (m, 6H), 6.96 (d, J=9.0 Hz, 1H), 7.02 (d, J=7.9 Hz, 1H),7.79 (d, J=14 Hz, 1H), 8.57 (s, 1H);

Anal. [C₂₄ H₃₀ FN₃ O₅ ]:

(Calcd., found): C, (62.73, 62.52); H, (6.58, 6.49); N, (9.14, 9.11); F,(4.13, 4.08).

3S,1R-1-cyclopropyl-6-fluoro-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

The protecting group was removed using method A, to provide the desiredproduct (0.94 g, 82.0%); mp >300° C.; ¹ H-NMR (NaOD+D₂ O) δ0.70-1.49 (m,9H), 1.73-2.05 (m, 2H), 2.49-2.70 (m, 1H), 2.73-3.00 (m, 1H), 3.03-3.49(m, 4H), 6.36 (d, J=7.3 Hz, 1H), 7.46 (d, J=15 Hz, 1H), 8.31 (s, 1H);Anal. [C₁₉ H₂₂ FN₃ O₃, 1.43 HCl, 0.71 H₂ O]:

(Calcd., found): C, (53.78, 53.78); H, (5.90, 5.83); N, (9.90, 9.81); F,(4.88, 4.66); Cl, (11.95, 11.96); [α]_(D) =+48° (c=0.97, 1N NaOH).

EXAMPLE 23S,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-t-butyloxycarbonylaminoethyl)-1-pyrrolidinyl]-1,4-oxo-3-quinolinecarboxylicacid

The desired product (1.09 g, 85%) was obtained starting from pyrrolidine22 and quinolone B; mp 217°-219° C.; ¹ H-NMR (CDCl₃) δ1.08-1.67 (m,16H), 1.73-2.05 (m, 1H), 2.07-2.50 (m, 2H), 3.27-3.97 (m, 6H), 4.37-4.60(m, 1H), 6.86 (d, J=7.4 Hz, 1H), 7.91 (d, J=14 Hz, 1H), 8.68 (s, 1H);Anal. [C₂₄ H₃₀ FN₃ O₅, 0.28 H₂ O]:

(Calcd., found): C, (62.05, 62.06); H, (6.63, 6.51); N, (9.04, 8.92); F,(4.09, 4.19).

3S,1S-1-cyclopropyl-6-fluoro-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

The protecting group was removed using method A to provide the desiredproduct (0.71 g, 78.1%), mp >300° C.; ¹ H-NMR (NaOD+D₂ O) δ0.62-1.51 (m,9H), 1.59-1.88 (m, 1H), 1.90-2.18 (m, 1H), 2.32-2.78 (m, 2H), 2.88-3.46(m, 4H), 6.27 (d, J=7.3 Hz, 1H), 7.37 (d, J=6.7 Hz, 1H), 8.28 (s, 1H);Anal. [C₁₉ H₂₂ FN₃ O₃, 1.64 HCl, 1.12 H₂ O]:

(Calcd., found): C, (51.94, 51.94); H, (5.94, 5.75); N, (9.56, 9.33); F,(4.32, 4.30); Cl, (13.23, 13.25); [α]_(D) =-62° (c=0.73, 1N NaOH).

EXAMPLE 33R,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-t-butyloxycarbonylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

The desired product (1.15 g, 84%) was obtained starting from pyrrolidine20 and quinolone B; mp 240°-241.5° C.; ¹ H-NMR (CDCl₃) δ1.10-1.66 (m,16H--contains 1.26 (d, J=6.5 Hz) and 1.47 (s)), 1.66-1.93 (m, 1H),2.08-2.48 (m, 2H), 3.38-3.90 (m, 6H), 4.40-4.60 (m, 1H), 6.86 (d, J=7.3Hz, 1H), 7.90 (d, J=14 Hz, 1H), 8.67 (s, 1H); Anal. [C₂₄ H₃₀ FN₃ O₅,0.09 H₂ O]:

(Calcd., found): C, (62.51, 62.18); H, (6.60, 6.18); N, (9.11, 9.14); F,(4.12, 4.81).

3R,1S-1-cyclopropyl-6-fluoro-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

The protecting group was removed using method B to provide the desiredproduct (0.69 g 74.8%), mp >300° C.; ¹ H-NMR (DMSO-d₆ +heat) δ1.08-1.23(m, 2H), 1.23-1.53 (m, 5H), 1.67-1.97 (m, 1H), 2.03-2.26 (m, 1H),2.35-2.63 (m, 1H), 3.17-3.83 (m, 1H), 3.40-3.57 (m, 1H), 3.57-3.92 (m,4H), 7.10 (d, J=7.4 Hz, 1H), 7.82 (d, J=15 Hz, 1H), 8.30 (br. s., 2H),8.59 (s, 1H); Anal. [C₁₉ H₂₂ FN₃ O₃ 1.00 HCl):

(Calcd., found): C, (57.65, 57.53); H, (5.60, 5.86); N, (10.61, 10.51);F, (4.80, 5.00); Cl, (8.96, 8.83); [α]_(D) =-58.8° (c=0.99, 1N NaOH).

EXAMPLE 43R,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-t-butyloxycarbonylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

The desired product (0.97 g, 73%) was obtained starting from pyrrolidine21 and quinolone B; mp 209.5°-211.5° C. dec.; ¹ H-NMR (CDCl₃) δ1.10 (m,16H--contains 1.24 (d, J=6.7 Hz) and 1.46 (s)), 1.72-2.05 (m, 1H),2.08-2.48 (m, 2H), 3.30-3.97 (m, 6H), 4.40-4.60 (m, 1H), 6.86 (d, J=7.5Hz, 1H), 7.90 (d, J=14 Hz, 1H), 8.67 (s, 1H); Anal. [C₂₄ H₃₀ FN₃ O₅,1.79 H₂ O]:

(Calcd., found): C, (58.62, 59.01); H, (6.88, 6.87); N, (8.54, 8.48); F,(3.86, 4.15).

3R,1R-1-cyclopropyl-6-fluoro-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

The protecting group was removed using method B to provide the desiredproduct (0.80 g, 89.6%), mp >300° C.; ¹ H-NMR (DMSO+heat) δ1.07-1.50 (m,7H), 1.72-2.00 (m, 1H), 2.12-2.37 (m, 1H), 2.37-2.65 (m, 1H), 3.18-3.51(m, 2H), 3.53-3.87 (m, 4H), 7.09 (d, J=7.9 Hz, 1H), 7.82 (d, J=14 Hz,1H), 8.18 (br. s., 1H), 8.59 (s, 1H); Anal. [C₁₉ H₂₂ FN₃ O₃, 1.00 HCl,2.56 H₂ O]:

(Calcd., found): C, (51.63, 51.26); H, (6.41, 6.56); N, (9.51, 9.44);Cl, (8.02, 8.19); F, (4.30, 4.80); [α]_(D) =-60.3° (c=0.95 1N NaOH).

EXAMPLE 53S,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-t-butyloxycarbonylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-caboxylicacid

The desired product (0.63 g, 88%) was obtained starting from pyrrolidine23 and quinolone A, mp 220°-220° C.; ¹ H-NMR (DMSO-d₆ +heat) δ0.97-1.27(m, 7H), 1.39 (s, 9H), 1.53-1.83 (m, 1H), 1.95-2.17 (m, 1H), 2.17-2.43(m, 1H), 3.40-3.83 (m, 4H), 3.83-4.13 (m, 2H), 6.98 (d, J=9.0 Hz, 1H),7.95 (d, J=13 Hz, 1H), 8.56 (s, 1H), 15.45 (s); Anal. [C₂₃ H₂₉ FN₄ O₅ ]:

(Calcd., found): C, (59.99, 59.75); H, (6.35, 6.37); N, (12.17, 12.21);F, (4.12, 4.29).

3S,1R-1-cyclopropyl-6-fluoro-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid

The protecting group was removed using method B to provide the desiredproduct (1.02 g, 74.1%), mp >300° C.; ¹ H-NMR (DMSO-d₆ +heat) δ0.93-1.17(m, 2H), 1.17-1.47 (m, 5H), 1.63-1.95 (m, 1H), 2.00-2.37 (m, 1H),2.33-2.63 (m, 1H), 3.20-3.47 (m, 1H), 3.50-3.87 (m, 3H), 3.90-4.25(m,2H), 8.00 (d, J=13 Hz, 1H), 8.30 (br. s., 1H), 8.58 (s, 1H); Anal.[C₁₈ H₂₁ FN₄ O₃, 1.00 HCl]:

(Calcd., found): C, (54.48, 54.47); H, (5.59, 5.44); N, (14.18, 13.88);Cl, (8.93, 8.72); F, (4.79, 5.09); [α]_(D) =+3.6° (c=1.00 1N NaOH).

EXAMPLE 63S,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-t-butyloxycarbonylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid

The desired product (0.78 g, 53%) was obtained starting from pyrrolidine22 and quinolone A; mp 208°-208.5° C. dec; ¹ H-NMR (DMSO-d₆ +heat)δ1.00-1.32 (m, 7H), 1.37 (s, 9H), 1.63-1.91 (m, 1H), 1.93-2.15 (m, 1H),2.18-2.43 (m, 1H), 3.38-3.80 (m, 4H), 3.80-4.12 (m, 2H), 6.95 (d, J=8.9Hz, 1H), 7.93 (d, J=13 Hz, 1H), 8.55 (s, 1H), 15.4 (s); Anal. [C₂₃ H₂₉FN₄ O₅, 1.09 H₂ O, 0.06 CH₃ CN]:

(Calcd., found): C, (57.54, 57.57); H, (6.56, 6.52); N, (11.78, 11.68);F, (3.94, 4.26).

3S,1S-1-cyclopropyl-6-fluoro-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid

The protecting group was removed using method B to provide the desiredproduct (0.65 g, 69.1%), mp >300° C.; ¹ H-NMR (DMSOd-₆ +heat) δ1.00-1.50(m, 7H), 1.65-2.00 (m, 1H), 2.10-2.35 (m, 1H), 2.37-2.67 (m, 1H),3.17-3.87 (m, 4H), 3.90-4.20 (m, 2H), 8.00 (d, J=13 Hz, 1H), 8.23 (br.s.), 8.58 (s, 1H); Anal. [C₁₈ H₂₁ FN₄ O₃, 1.00 HCl]:

(Calcd., found): C, (54.48, 54.42); H, (5.59, 5.41); N, (14.18, 13.86);Cl, (8.93, 9.10); F, (4.79, 4.88); [α]_(D) =+13° (c=1.00, 1N NaOH).

p EXAMPLE 73R,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-t-butyloxycarbonylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid

The desired product (0.76 g, 92%) was obtained starting from pyrrolidine20 and quinolone A; mp 216.5°-217.0° C.; ¹ H-NMR (DMSO-d₆) δ1.00-1.27(m, 7H), 1.39 (s, 9H), 1.56-1.83 (m, 1H), 1.95-2.17 (m, 1H), 2.18-2.43(m, 1H), 3.40-3.83 (m, 4H), 3.83-4.10 (m, 2H), 6.98 (d, J=8.6 Hz, 1H),7.94 (d, J=13 Hz, 1H), 8.56 (s, 1H), 15.4 (s); Anal. [C₂₃ H₂₉ N₄ O₅ ]:

(Calcd., found): C, (59.99, 59.75); H, (6.30, 6.20); N, (12.17, 12.03);F, (4.12, 3.85).

3R,1S-1-cyclopropyl-6-fluoro-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid

The protecting group was removed using method B to provide the desiredproduct (0.64 g, 88.7%), mp >300° C.; ¹ H-NMR (DMSO-d₆ +heat) δ0.97-1.18(m, 2H), 1.18-1.50 (m, 5H), 1.65-1.95 (m, 1H), 2.02-2.27 (m, 1H),2.33-2.63 (m, 1H), 3.20-3.40 (m, 1H), 3.47-3.87 (m, 3H), 3.88-4.25 (m,2H), 8.00 (d, J=13 Hz, 1H), 8.26 (br. s.), 8.58 (s, 1H); Anal. [C₁₈ H₂₁FN₄ O₃, 1.00 HCl, 0.22 H₂ O]:

(Calcd., found): C, (53.94, 53.95); H, (5.64, 5.51); N, (13.98, 13.95);Cl, (8.44, 8.66); F, (4.73, 4.62); [α]_(D) =-4.8° (c=1.03, 1N NaOH).

EXAMPLE 83R,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-t-butyloxycarbonylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid

The desired product (0.56 g, 81%) was obtained starting from pyrrolidine21 and quinolone A; mp 210.0°-210.5° C.; ¹ H-NMR (DMSO) δ1.00-1.28 (m,7H), 1.38 (s, 9H), 1.63-1.90 (m, 1H), 1.93-2.15 (m, 1H), 2.17-2.45 (m,1H), 3.33-3.83 (m, 4H), 3.83-4.10 (m, 2H), 6.95 (d, J=8.6 Hz, 1H), 7.95(d, J=13 Hz, 1H), 8.56 (s, 1H), 15.4 (s); Anal. [C₂₃ H₂₉ FN₄ O₅, 0.78 H₂O, 0.10 CH₃ N]:

(Calcd., found): C, (58.22, 58.12); H, (6.50, 6.39); N, (12.00, 11,68);F, (3.97, 4.21).

3R,1R-1-cyclopropyl-6-fluoro-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-1[-naphthyridine-3-carboxylicacid

The protecting group was removed using method B to provide the desiredcompound (0.67 g, 77.1%), mp >300° C.; ¹ H-NMR (DMSO-d₆ +heat)δ1.00-1.47 (m, 7H), 1.68-2.00 (m, 1H), 2.11-2.35 (m, 1H), 2.35-2.67 (m,1H), 3.17-3.87 (m, 4H), 3.90-4.17 (m, 2H), 8.00 (d, J=13 Hz, 1H), 8.30(br. s.), 8.58 (s, 1H); Anal. [C₁₈ H₂₁ FN₄ O₃, 1.00 HCl]:

(Calcd., found): C, (54.48, 54.31); H, (5.59, 5.68); N, (14.18, 14.08);Cl, (8.93, 8.58); F, (4.79, 4.44); [α]_(D) =-13.9° (c=1.09%, 1N NaOH);HPLC=99.7%.

EXAMPLE 93R,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-ethylaminoethyl)-1-pyrrolidinyl]-8-trifluoromethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

The quinolone (D, 0.90 g, 2.7 mmol), pyrrolidine (45) (0.43 g, 3.0mmol), and triethylamine (0.42 mL) were dissolved in acetonitrile (25mL) and heated to reflux for 20 hours. The reaction was cooled to 5° C.and the solid collected by filtration. This solid was washed with coldacetonitrile and dried under vacuum at 50° C. for 60 hours. This yielded0.83 g of the title compound.

Calcd. for C₂₂ H₂₅ F₄ N₃ O₃, 0.5 H₂ O: C, 56.89; H, 5.64; N, 9.05 Found:C, 56.98; H, 5.69; N, 9.12.

¹ H-NMR (CD₃ OD) δ8.63 (s, 1H), 7.76 (d, 1H, J=14.5 Hz), 4.00-3.55(broad m, 6H), 3.20-2.90 (m, 2H), 2.65-2.50 (m, 1H), 2.25-2.10 (m, 1H),1.90-1.80 (m, 1H), 1.40-1.10 (m, 8H), 1.00-1.85 (m, 1H), 0.80-0.70 (m,1H).

EXAMPLE 103R,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-ethylaminoethyl)-1-pyrrolidinyl]-8-trifluoromethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

The quinolone (D, 0.90 g, 2.7 mmol), pyrrolidine (44) (0.43 g, 3.0mmol), and triethylamine (0.42 mL) were dissolved in acetonitrile (25mL) and heated to reflux for 20 hours. The reaction was cooled to 5° C.and the solid collected by filtration. This solid was washed with coldacetonitrile and dried under vacuum at 50° C. for 60 hours. This yielded0.27 g of the title compound. The reaction filtrate was evaporated to asolid and triturated with water. The solid collected was dried at 50° C.for 24 hours to give an additional 0.62 g of the title compound.

Calcd. for C₂₂ H₂₅ F₄ N₃ O₃.1.14 H₂ O C, 55.51; H, 5.78; N, 8.83 Found:C, 55.13; H, 5.37; N, 8.47.

¹ H-NMR (CD₃ OD) δ8.58 (s, 1H), 7.74 (d, 1H, J=14.7 Hz), 3.95-3.45 (m,5H), 3.30-3.15 (m, 2H), 3.10-2.95 (m, 1H), 2.50-2.30 (m, 1H), 2.20-2.05(m, 1H), 1.80-1.60 (m, 1H), 1.45-1.30 (m, 6H), 1.25-1.05 (m, 2H),0.95-0.80 (m, 1H), 0.75-0.60 (m, 1H).

EXAMPLE 113S,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-ethylaminoethyl)-1-pyrrolidinyl-8-trifluoromethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

The quinolone (D, 0.90 g, 2.7 mmol), pyrrolidine (47) (0.43 g, 3.0mmol), and triethylamine (0.42 mL) were dissolved in acetonitrile (25mL) and heated to reflux for 20 hours. The reaction was cooled to 5° C.and the solid collected by filtration. This solid was washed with coldacetonitrile and dried under vacuum at 50° C. for 60 hours. This yielded0.33 g of the title compound. The reaction filtrate was evaporated to asolid and triturated with water. The solid collected was dried at 50° C.for 24 hours to give an additional 0.73 g of the title compound.

Calcd. for C₂₂ H₂₅ F₄ N₃ O₃, 0.95 H₂ O: C, 55.92; H, 5.74; N, 8.89Found: C, 55.91; H, 5.70; N, 9.06.

¹ H-NMR (CD₃ OD) δ8.55 (s, 1H), 7.73 (d, 1H, J=14 Hz), 3.95-3.45 (m,5H), 3.30-3.10 (m, 2H), 3.05-2.90 (m, 1H), 2.50-2.30 (m, 1H), 2.20-2.05(m, 1H), 1.80-1.60 (m, 1H), 1.50-1.30 (broad featureless peak, 6H),1.30-1.05 (m, 2H), 0.95-0.80 (m, 1H), 0.75-0.60 (m, 1H).

EXAMPLE 123S,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-ethylaminoethyl)-1-pyrrolidinyl]-8-trifluoromethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

The quinolone (D, 0.90 g, 2.7 mmol), pyrrolidine (46) (0.43 g, 3.0mmol), and triethylamine (0.42 mL) were dissolved in acetonitrile (25mL) and heated to reflux for 20 hours. The reaction was cooled to 5° C.and the solid collected by filtration. This solid was washed with coldacetonitrile and dried under vacuum at 50° C. for 60 hours. This yielded0.92 g of the title compound.

Calcd. for C₂₂ H₂₅ F₄ N₃ O₃, 1.34 H₂ O: C, 55.10; H, 5.82; N, 8.76Found: C, 54.84; H, 5.55; N, 9.16.

¹ H-NMR (CD₃ OD) δ8.67 (s, 1H), 7.79 (d, 1H, 14.5 Hz), 4.00-3.55 (m,6H), 3.20-3.10 (m, 1H), 3.10-2.90 (m, 1H), 2.65-2.50 (m, 1H), 2.30-2.15(m, 1H), 1.90-1.70 (m, 1H), 1.40-1.10 (m, 8H), 1.00-0.90 (m, 1H),0.85-0.70 (m, 1H).

EXAMPLE 133R,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-ethylaminoethyl)-1-pyrrolidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

The quinolone (B, 0.50 g, 1.9 mmol), pyrrolidine (45) (0.30 g, 2.1mmol), and triethylamine (0.30 mL) were dissolved in acetonitrile (7 mL)and heated to reflux for 20 hours. The reaction became very viscous uponheating and an additional 5 mL of acetonitrile was added. The reactionwas cooled to 5° C. and the solid collected by filtration. This solidwas washed with cold acetonitrile and dried under vacuum at 50° C. for18 hours. This yielded 0.70 g of the title compound.

Calcd. for C₂₁ H₂₆ FN₃ O₃, 0.33 HF: C, 64.01; H, 6.73; N, 10.66; F, 6.41Found: C, 63.73; H, 6.70; N, 10.55; F, 6.17.

¹ H-NMR (TFA) δ9.18 (s, 1H), 8.13 (d, 1H, J=13.5 Hz), 7.33 (d, 1H, J=6.7Hz), 7.20-6.90 (broad m, 1H), 4.30-4.15 (m, 1H), 4.10-3.30 (m, 7H),3.00-2.80 (m, 1H), 2.70-2.55 (m, 1H), 2.20-2.05 (m, 1H), 1.75-1.60 (m,5H), 1.53 (t, 3H, J=7.1 Hz), 1.50-1.30 (m, 2H).

EXAMPLE 143R,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-ethylaminoethyl)-1-pyrrolidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

The quinolone (B, 0.50 g, 1.9 mmol), pyrrolidine (44) (0.30 g, 2.1mmol), and triethylamine (0.30 mL) were dissolved in acetonitrile (7 mL)and heated to reflux for 20 hours. The reaction became very viscous uponheating and an additional 5 mL of acetonitrile was added. The reactionwas cooled to 5° C. and the solid collected by filtration. This solidwas washed with cold acetonitrile and dried under vacuum at 50° C. for18 hours. This yielded 0.63 g of the title compound.

Calcd. for C₂₁ H₂₆ FN₃ O₃, 0.6 HF: C, 63.14; H, 6.71; N, 10.52; F, 7.61Found: C, 62.80; H, 6.66; N, 10.73; F, 7.63.

¹ H-NMR (CD₃ OD) δ8.45 (s, 1H), 7.51 (d, 1H, J=14.4 Hz), 3.85-3.75 (m,1H), 3.70-3.40 (m, 4H), 3.25-2.85 (m, 3H), 3.55-3.45 (m, 1H), 2.25-2.10(m, 1H), 1.95-1.80 (m, 1H), 1.40-1.25 (m, 8H), 1.20-1.10 (m, 2H).

EXAMPLE 153S,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-ethylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4oxo-4-quinolinecarboxylicacid

The quinolone (B, 0.50 g, 1.9 mol), pyrrolidine (47) (0.30 g, 2.1 mol),and triethylamine (0.30 mL) were dissolved in acetonitrile (7 mL) andheated to reflux for 20 hours. The reaction became very viscous uponheating and an additional 5 mL of acetonitrile was added. The reactionwas cooled to 5° C. and the solid collected by filtration. This solidwas washed with cold acetonitrile and dried under vacuum at 50° C. for18 hours. This yielded 0.63 g of the title compound.

Calcd. for C₂₁ H₂₆ FN₃ O₃, 0.75 HF: C, 62.67; H, 6.70; N, 10.44; F, 8.26Found: C, 62.74; H, 6.72; N, 10.71; F, 8.20.

¹ H-NMR (TFA) δ9.18 (s, 1H), 8.13 (d, 1H, J=13.5 Hz), 7.34 (d, 1H, 7.1Hz), 7.10-6.90 (broad m, 1H), 4.45-4.30 (m, 1H), 4.05-3.60 (m, 5H),3.60-3.50 (m, 1H), 3.50-3.30 (m, 1H), 3.00-2.75 (m, 1H), 2.55-2.40 (m,1H), 2.20-1.95 (m, 1H), 1.70-1.55 (m, 5H), 1.51 (t, 3H, J=7.2 Hz),1.45-1.30 (m, 2H).

EXAMPLE 163S,1S-1-cyclopropyl-6-fluoro-7-[3-(1-ethylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-3quinolinecarboxylicacid

The quinolone (B, 0.50 g, 1.9 mol), pyrrolidine (46) (0.30 g, 2.1 mol),and triethylamine (0.30 mL) were dissolved in acetonitrile (7 mL) andheated to reflux for 20 hours. The reaction became very viscous uponheating and an additional 5 mL of acetonitrile was added. The reactionwas cooled to 5° C. and the solid collected by filtration. This solidwas washed with cold acetonitrile and dried under vacuum at 50° C. for18 hours. This yielded 0.69 g of the title compound.

Calcd. for C₂₁ H₂₆ FN₃ O₃, 0.6 HF: C, 63.14; H, 6.71; N, 10.52; F, 7.61Found: C, 63.07; H, 6.73; N, 10.72; F, 7.85.

EXAMPLE 173R,1R-1-cyclopropyl-6-fluoro-7-3-(1-N-ethylaminoethyl)1-pyrrolidinyl]-8-methoxy-1,4-dihydro-4oxo-3-quinolinecarboxylicacid

The1-cyclopropyl-6,8-difluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (E) borondifluoride complex (1.20 g, 3.5 mmol), and pyrrolidine(45) (1.00 g, 7.0 mmol) were dissolved in acetonitrile (20 mL) andstirred for four hours, then allowed to stand for 96 hours. The reactionmixture was evaporated to an oil and dissolved in 95% ethanol (25 mL)containing 5 mL of triethylamine and heated to reflux for four hoursthen allowed to stand for 24 hours. The mixture was diluted with 300 mLof ethanol and evaporated and redissolved in water (50 mL) andreevaporated to an oil. This oil was purified flash chromatography usingsilica gel eluting with methylene chloride (1900 mL), 2.6% NH₃ inmethanol (95 mL), water (5 mL). The appropriate fractions were combinedand evaporated to give the title compound (0.96 g).

Calcd. for C₂₂ H₂₈ FN₃ O₄.0.84 CH₂ Cl₂ C, 56.12; H, 6.12; N, 8.60;Found: C, 56.80; H, 6.29; N, 8.86.

¹ H-NMR (CD₃ OD) δ8.67 (s, 1H), 7.59 (d, 1H, J=14 Hz), 4.10-3.95 (m,1H), 3.90-3.75 (m, 1H), 3.70-3.55 (m, 2H), 3.42 (s, 3H), 3.42-3.25 (m,2H, underlies singlet and CD₃ OD peak), 3.20-3.05 (m, 1H), 3.15-2.95 (m,1H), 2.65-2.45 (m, 1H), 2.25-2.10 (m, 1H), 1.90-1.70 (m, 1H), 1.40-1.30(m, 6H), 1.30-0.95 (m, 3H), 0.90-0.70 (m, 1H).

EXAMPLE 183R,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-ethylaminoethyl)-1-pyrrolidinyl]-8-methoxy-1,4-dihydro-4-3-quinolinecarboxylicacid

Using pyrrolidine 44, the procedure described above was employed toprepare 0.78 g of the title compound.

Calcd. for C₂₂ H₂₈ FN₃ O₄.1.22 CH₂ Cl₂ : C, 53.52; H, 5.89; N, 8.06;Found: C, 53.50; H, 6.04; N, 8.27.

¹ H-NMR (CD₃ OD) δ8.70 (s, 1H), 7.55 (d, 1H, J=13.9 Hz), 4.15-4.05 (m,1H), 3.90-3.70 (m, 2H), 3.80-3.55 (m, 1H), 3.55-3.40 (m and s, 4H,singlet at 3.50), 3.40-3.35 (m, 1H, overlapped with CD₃ OD peak),3.35-3.20 (m, 1H), 3.20-3.05 (m, 1H), 2.55-2.40 (m, 1H), 2.25-2.10 (m,1H), 1.90-1.70 (m, 1H), 1.45-1.30 (m, 6H), 1.30-1.20 (m, 1H), 1.20-1.00(m, 2H), 0.95-0.80 (m, 1H).

EXAMPLE 193S,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-ethylaminoethyl)1-pyrrolidinyl]-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

Using pyrrolidine 47, the procedure described above was employed toprepare 1.14 g of the title compound.

Calcd. for C₂₂ H₂₈ FN₃ O₄.0.21 CH₂ Cl₂ : C, 6.28; H, 6.58; N, 9.58.Found: C, 61.24; H, 6.70; N, 9.71.

¹ H-NMR (CD₃ OD) δ8.57 (s, 1H), 7.59 (d, 1H, J=13.9 Hz), 4.04-3.90 (m,1H), 3.85-3.65 (m, 2H), 3.60-3.45 (m, 1H), 3.25 (s, 3H), 3.20-3.05 (m,3H), 3.05-2.95 (m, 1H), 2.40-2.10 (m, 2H), 1.80-1.60 (m, 1H), 1.45-1.30(m, 6H), 1.25-1.10 (m, 2H), 1.10-0.95 (m, 1H), 0.80-0.65 (m, 1H).

EXAMPLE 203S,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-ethylaminoethyl)1-pyrrolidinyl]-8-methoxy-1,4-dihydro-4-oxo-3quinolinecarboxylicacid

Using pyrrolidine 46, the procedure described above was employed toprepare 0.93 g of the title compound.

Calcd. for C₂₂ H₂₈ FN₃ O₄.0.18 CH₂ Cl₂ : C, 61.56; H, 6.61; N, 9.71.Found: C, 61.55; H, 6.69; N, 9.79. MS (EI) 417 (M+), 372, 357, 313, 287,72 (base).

¹ H-NMR (CD₃ OD) δ8.60 (s, 1H), 7.58 (d, 1H, J=13.7 Hz), 4.10-3.95 (m,1H), 3.85-3.70 (m, 1H), 3.70-3.50 (m, 2H), 3.31 (s, 3H), 3.30-3.20 (m,2H), 3.20-3.10 (m, 1H), 3.05-2.90 (m, 1H), 2.65-2.45 (m, 1H), 2.20-2.05(m, 1H), 1.85-1.65 (m, 1H), 1.36 (t, 3H, J=7.1 Hz), 1.30 (t, 3H, J=6.7Hz), 1.25-1.05 (m, 2H), 1.05-0.95 (m, 1H), 0.85-0.70 (m, 1H).

EXAMPLE 213R,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4oxo-1,8-naphthyridine-3-carboxylicacid

From 0.85 g (3 mmol) of 7-chloro-1,8-naphthyridine A, 0.70 g (3.1 mmol)of pyrrolidine 60, and 0.46 g (4.5 mmol) of triethylamine, there wasobtained 0.84 g (59%) of the title compound after column chromatography(silica gel, dichloromethane/methanol 20:1); mp 233°-234° C.

[α]_(D) =-48° (c=0.56, chloroform).

¹ H-NMR (250 MHz, CDCl₃) δ0.99-1.10 (m, 2H), 1.18-1.26 (m, 5H), 1.43 and1.46 (2×s, 9H), 1.68-1.87 (m, 1H), 2.07-2.23 (m, 1H), 2.38-2.60 (m, 1H),2.78 (br. s, 3H), 3.40-3.68 (m, 2H), 3.72-4.34 (m, 4H), 7.89 (d, 1H,J=12.5 Hz), 8.61 (s, 1H), 15.12-15.25 (m, 1H).

Anal . Calcd. for C₂₄ H₃₁ FN₄ O₅ : C, 60.75; H, 6.58; N, 11.81. Found:C, 60.67; H, 6.87; N, 11.50.

3R,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-methylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid

From 0.75 g (1.6 mmol) of the above protected derivative, the titlecompound (0.44 g) was obtained using Method C as an off-white solid;mp >280° C.

¹ H-NMR (TFA) δ1.20-1.35 (m, 2H), 1.47-1.60 (m, 2H), 1.65 (dist. d, 3H,J=5.8 Hz), 1.90-2.20 (m, 1H), 2.35-2.55 (m, 1H), 2.85-3.10 (m, 1H), 3.04(s, 3H), 3.60-3.79 (m, 1H), 3.82-4.20 (m, 3H), 4.26-4.48 (m, 1H),4.51-4.78 (m, 1H), 7.20-7.55 (m, 1H), 8.11 (d, 1H, J=11.6 Hz), 9.16 (s,1H).

Anal . Calcd. for C₁₉ H₂₃ FN₄ O₃.1.0 HCl.0.2 H₂ O: C, 55.06; H, 5.93; N,13.52; Cl, 8.55 Found: C, 54.74; H, 5.79; N, 12.89; Cl, 9.24.

EXAMPLE 223R,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid

From 0.73 g (2.6 mmol) of 7-chloro-1,8-naphthyridine A, 0.60 g (2.6mmol) of pyrrolidine 61, and 0.38 g (3.8 mmol) of triethylamine, therewas obtained 1.03 g (84%) of the title compound after columnchromatography (silica gel, dichloro-methane/methanol 10:1); mp212°-213° C.

[α]_(D) =-13° (c 1.00, EtOH).

¹ H-NMR (CDCl₃) δ0.90-1.10 (m, 2H), 1.12-1.30 (m, 5H), 1.49 (s, 9H),1.70-1.92 (m, 1H), 1.94-2.15 (m, 1H), 2.30-2.55 (m, 1H), 2.78 and 2.81(2×s, 3H), 3.35-3.55 (m, 1H), 3.55-3.67 (m, 1H), 3.67-3.88 (m, 1H),3.88-4.15 and 4.17-4.30 (m, 3H), 7.90 (d, 1H, J=12.6 Hz), 8.62 (s, 1H),14.55-14.62 (m, 1H).

Anal. Calcd. for C₂₄ H₃₁ FN₄ O₅.0.40 H₂ O: C, 59.84; H, 6.65; N, 11.63Found: C, 59.96; H, 6.48; N, 11.54.

3R,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-methylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid

Using Method B on the above protected derivative (1.00 g, 2.1 mmol),there was obtained the title compound (0.85 g) as an off-white solid;mp >280° C.

¹ H-NMR (TFA) δ1.20-1.40 (m, 2H), 1.45-1.75 (m, 5H), 1.97-2.30 (m, 1H),2.50-2.70 (m, 1H), 2.80-3.18 (m, 1H), 3.05 (s, 3H), 3.53-4.23 (m, 4H),4.30-4.60 (m, 2H), 7.20-7.50 (m, 1H), 8.12 (d, 1H, J=11.6 Hz), 9.18 (s,1H).

Anal. Calcd. for C₁₉ H₂₃ FN₄ O₃.1.0 HCl.0.75 H₃ O: C, 53.77; H, 6.06; N,13.20; Cl, 8.35; F, 4.48 Found: C, 53.70; H, 5.82; N, 13.09; Cl, 8.68;F, 4.48.

EXAMPLE 233S,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid

From 0.76 g (2.7 mmol) of 7-chloro-1,8-naphthyridine A, 0.75 g (3.3mmol) of pyrrolidine 63, and 0.41 g (4.1 mmol) of triethylamine, therewas obtained 0.77 g (60%) of the title compound. Concentration of thefiltrate and washings provided additional product (0.40 g, 31%); mp232°-233° C.

[α]_(D) =43° (c=0.50, chloroform).

¹ H-NMR (CDCl₃) δ0.99-1.08 (m, 2H), 1.19-1.27 (m, 5H), 1.42 and 1.46(2×s, 9H), 1.65-1.80 (m, 1H), 2.07-2.20 (m, 1H), 2.36-2.50 (m, 1H), 2.77and 2.80 (2×s, 3H), 3.75-4.13 (m, 4H), 7.92 (d, 1H, J=12.4 Hz), 8.64 (s,1H), 15.20 and 15.24 (2×s, 1H).

Anal. Calcd. for C₂₄ H₃₁ FN₄ O₅. 2/3 H₂ O: C, 59.26; H, 6.70; N, 11.51Found: C, 59.24; H, 6.41; N, 11.44.

3S,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-methylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid

Using Method C on 1.20 g (2.5 mmol) of the above protected derivative,there was obtained the title compound (1.07 g); mp >280° C.

¹ H-NMR (250 MHz, d₆ -DMSO+TFA): 0.97-1.30 (m, 7H), 1.70-1.86 (m, 1H),2.05-2.19 (m, 1H), 2.40-2.70 (m, 1H), 2.67 and 2.76 (2×s, 3H), 3.24-3.39(m, 1H), 3.43-3.78 (m, 3H), 3.90-4.01 1H), 4.04-4.20 (m, 1H), 8.11 (d,1H, J=13.0 Hz), 8.72 (s, 1H).

Anal. Calcd. for C₁₉ H₂₃ FN₄ O₃.1.0 HCl.0.6 H₂ O: C, 54.12; H, 6.02; N,13.29; F, 4.51 Found: C, 53.94; H, 6.39; N, 12.90; F, 4.19.

EXAMPLE 243S,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid

From 0.71 g (2.5 mmol) of 7-chloro-1,8-naphthyridine A, 0.70 g (3.1mmol) of pyrrolidine 62, and 0.40 g (4.0 mmol) of triethylamine, therewas obtained 0.98 g (83%) of the title compound; mp 218.0°-219.5° C.

[α]_(D) =28° (c=1.04, chloroform).

¹ H-NMR (CDCl₃) δ1.02-1.07 (m, 2H), 1.18-1.26 (m, 5H), 1.48 (s, 9H),1.75-1.93 (m, 1H), 1.97-2.15 (m, 1H), 2.36-2.56 (m, 1H), 2.77 and 2.81(2×s, 3H), 3.41-3.56 (m, 1H), 3.58-3.67 (m, 1H), 3.70-3.84 (m, 1H),3.93-4.34 (m, 3H), 7.95 (d, 1H, J=12.5 Hz), 8.66 (s, 1H), 15.15-15.23(m, 1H).

Anal. Calcd. for C₂₄ H₃₁ FN₄ O₅.0.2 H₂ O: C, 60.29; H, 6.62; N, 11.72Found: C, 59.91; H, 6.74; N, 11.67.

3S,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-methylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid

Using Method B on 1.20 g (2.5 mmol) of the above protected derivativethere was obtained the title compound (0.75 g). Concentration of themother liquor provided additional product (0.28 g); mp >280° C.

[α]_(D) =20° (c=1.08, 1N NaOH).

¹ H-NMR (CDCl₃) δ1.01-1.10 (m, 2H), 1.15-1.25 (m, 2H), 1.29 (d, 3H,J=6.4 Hz), 1.78-1.99 (m, 1H), 2.22-2.37 (m, 1H), 2.50-2.70 (m, 1H), 2.58(s, 3H), 3.30-3.60 (m, 2H), 3.62-3.80 (m, 2H), 3.92-4.10 (m, 2H), 7.92(d, 1H, J=12.7 Hz), 8.53 (s, 1H), 8.98-9.16 (m, 1H), 9.17-9.30 (m, 1H),15.37 (br. s, 1H).

Anal. Calcd. for C₁₉ H₂₃ FN₄ O₃.1.0 HCl.0.5 H₂ O: C, 54.35; H, 6.00; N,13.34; Cl, 8.44 Found: C, 54.47; H, 5.97; N, 13.28, Cl, 8.48.

EXAMPLE 253R,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-pyrrolidinyl-8-chloro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

From 0.90 g (3.0 mmol) of quinolone C, 0.70 g (3.1 mmol) of pyrrolidine60, and 0.61 g (6.0 mmol) of triethylamine, there was obtained 1.22 g(80%) of the title compound after recrystallization fromdichloromethane/heptane.

[α]_(D) =180° (c=1.05, chloroform).

¹ H-NMR (CDCl₃) δ0.84-0.95 (m, 1H), 0.96-1.09 (m, 1H), 1.23 (dist. d,3H, J=5.0 Hz), 1.30-1.58 (m, 2H), 1.45 (s, 9H), 1.62-1.81 (m, 1H),2.06-2.21 (m, 1H), 2.37-2.57 (m, 1H), 2.7 6 and 2.78 (2×s, 3H),3.35-3.85 (m, 3H), 3.93-4.17 (m, 2H), 4.22-4.39 (m, 1H), 7.81 and 7.83(2×d, 1H, J=13.4 Hz), 8.83 (s, 1H), 14.67 and 14.71 (2×br. s, 1H).

Anal. Calcd. for C₂₅ H₃₁ ClFN₃ O₅ : C, 59.11; H, 6.15; N, 8.27; Cl, 6.98Found: C, 59.03; H, 6.21; N, 8.22; Cl, 7.17.

3R,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-methylaminoethyl)-1)-1-pyrrolidinyl]-8-chloro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

Using 1.15 g (2.3 mmol) of the above quinolone, hydrolysis of thetert-butoxycarbonyl group according to general Method C provided thetitle compound (0.10 g) as the hydrochloride salt.

¹ H-NMR (TFA) δ1.30-1.47 (m, 2H), 1.56-1.84 (m, 5H), 2.01-2.22 (m, 1H),2.40-2.59 (m, 1H), 2.83-3.15 (m, 4H), 3.57-3.77 (m, 1H), 3.80-4.10 (m,4H), 4.23-4.50 (m, 1H), 7.20-7.60 (br m, 1H), 8.16 (br d, 1H, J=13 Hz,9.18 (s, 1H), 11.62 (m, 1H).

EXAMPLE 263R,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-pyrrolidinyl]-8-chloro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

From 0.99 g (3.3 mmol) of quinolone C, 0.75 g (3.3 mmol) of pyrrolidine61, and 0.51 g (5.0 mmol) of triethylamine, there was obtained 1.66 g(99%) of the title compound after column chromatography (silica gel,dichloromethane/methanol 10:1).

[α]_(D) =-146° (c=0.50, EtOH).

¹ H-NMR (CDCl₃) δ0.80-1.08 (m, 2H), 1.10-1.35 (m, 2H), 1.16 (d, 3H,J=6.7 Hz), 1.48 (s, 9H), 1.67-1.85 (m, 1H), 1.90-2.15 (m, 1H), 2.30-2.50(m, 1H), 2.70-2.83 (m, 3H), 3.42-3.60 (m, 3H), 3.75-4.16 (m, 2H),4.18-4.37 (m, 1H), 7.91 (d, 1H, J=13.3 Hz), 8.86 (s, 1H), 14.60-14.80(m, 1H).

Anal. Calcd. for C₂₅ H₃₁ ClFN₃ O₅.0.20 H₂ O: C, 58.69; H, 6.19; N, 8.21Found: C, 58.66; H, 5.98; N, 8.03.

3R,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-methylaminoethyl)-1-pyrrolidinyl]-8-chloro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

Using Method B on 1.58 g (3.1 mmol) of the above protected quinolone,the title compound was obtained (0.79 g) as a solid; mp >280° C.

[α]_(D) =-109° (c=0.93, methanol).

¹ H-NMR (CD₃ OD) δ0.89-1.10 (m, 2H), 1.16-1.45 (m, 2H), 1.40 (d, 3H,J=6.6 Hz), 1.83-2.00 (m, 1H), 2.2 6-2.40 (m, 1H), 2.55-2.70 (m, 1H),2.77 (s, 3H), 3.28-3.44 (m, 2H), 3.60-3.69 (m, 3H), 3.91-4.02 (m, 1H),4.39-4.48 (m, 1H), 7.84 (d, 1H, J=13.3 Hz), 8.91 (s, 1H).

Anal. Calcd. for C₂₀ H₂₃ ClFN₃ O₃.1.0 HCl.1.0 H₂ O: C, 51.96; H, 5.67;N, 9.09; Cl, 15.34 Found: C, 52.05; H, 5.73; N, 9.22; Cl, 15.42.

EXAMPLE 273R,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-pyrrolidinyl]-8-trifluoromethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

From 1.00 g (3.0 mmol) of quinolone D, 0.71 g (3.1 mmol) of pyrrolidine60, and 0.61 g (6.0 mmol) of triethylamine, there was obtained 1.31 g(81%) of the title compound after recrystallization fromdichloromethane/heptane; mp 175°-177° C.

[α]_(D) =-332° (c=0.13, chloroform).

¹ H-NMR (CDCl₃) δ0.70-0.83 (m, 1H), 0.85-1.02 (m, 1H), 1.17-1.38 (m,2H), 1.22 (d, 3H, J=6.7 Hz), 1.46 (s, 9H), 1.65-1.80 (m, 1H), 2.05-2.19(m, 1H), 2.37-2.50 (m, 1H), 2.75 and 2.76 (2×s, 3H), 3.50-4.32 (m, 6H),7.90 and 7.93 (2×d, 1H, J=14.6 Hz), 8.77 (s, 1H), 14.76-14.82 (m, 1H).

Anal. Calcd. for C₂₆ H₃₁ F₄ N₃ O₅.0.50 H₂ O: C, 56.72; H, 5.86; N, 7.63Found: C, 56.63; H, 5.64; N, 7.56.

3R,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-methylaminoethyl)-1-pyrrolidinyl]-8-trifluoromethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

Using Method B on 1.10 g (2.0 mmol) of the above protected quinolone,there was obtained the title compound (0.94 g); mp 210°-212° C.

[α]_(D) =-234° (c=1.03, methanol).

¹ H-NMR (CD₃ OD) δ0.88-1.10 (m, 2H), 1.22-1.37 (m, 2H), 1.43 (d, 3H,J=6.3 Hz), 1.81-2.00 (m, 1H), 2.18-2.31 (m, 1H), 2.60-2.90 (m, 1H), 2.77(s, 3H), 3.35-3.50 (m, 1H), 3.63-4.20 (m, 5H), 7.71 (d, 1H, J=14.3 Hz),8.85 (s, 1H).

Anal. Calcd. for C₂₁ H₂₃ F₄ N₃ O₃.1.0 HCl.1.5 H₂ O: C, 49.96; H, 5.39;N, 8.32; Cl, 7.02; F, 15.05 Found: C, 49.84; H, 5.12; N, 8.56; Cl, 7.81;F, 14.67.

EXAMPLE 283R,1R-cyclopropyl-6-fluoro-7-[3-(1-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-pyrrolidinyl]-8-trifluoromethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

From 1.03 g (3.1 mmol) of quinolone D, 0.74 g (3.2 mmol) of pyrrolidine61, and 0.61 g (6.0 mmol) of triethylamine, there was obtained 1.15 g(69%) of the title compound after successive column chromatography(silica gel, dichloromethane/methanol 40:1) and recrystallization fromdichloro-methane/heptane.

[α]_(D) =-238° (c=0.10, chloroform).

¹ H-NMR (CDCl₃) δ0.75-1.10 (m, 2H), 1.12-1.40 (m, 2H), 1.19 (d, 3H,J=6.5 Hz), 1.49 (s, 9H), 1.70-1.94 (m, 1H), 1.97-2.10 (m, 1H), 2.36-2.50(m, 1H), 2.77 and 2.80 (2×s, 3H), 3.55-4.30 (m, 6H), 7.89 (d, 1H, J=14.3Hz), 8.78 (s, 1H), 14.73-14.78 (m, 1H).

Anal. Calcd. for C₂₆ H₃₁ F₄ N₃ O₅.0.30 H₂ O: C, 57.10; H, 5.82; N, 7.68;F, 13.89 Found: C, 57.14; H, 5.61; N, 7.42; F, 13.71.

3R,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-methylaminoethyl)-1-pyrrolidinyl]-8-trifluoromethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

Using Method B on 1.05 g (1.93 mmol) of the above protected quinolone,there was obtained the title compound (0.93 g) as a light yellow solid;mp 261°-262° C.

[α]_(D) =-259° (c=0.72, methanol).

¹ H-NMR (CD₃ OD) δ0.80-0.95 (m, 1H), 0.96-1.09 (m, 1H), 1.20-1.45 (m,2H), 1.39 (d, 3H, J=6.6 Hz), 1.80-2.00 (m, 1H), 2.26-2.40 (m, 1H),2.56-2.70 (m, 1H), 2.77 (s, 3H), 3.33-3.46 (m, 1H), 3.70-3.93 (m, 3H),3.97-4.14 (m, 2H), 7.84 (d, 1H, J=14.4 Hz), 8.86 (s, 1H).

Anal. Calcd. for C₂₁ H₂₃ F₄ N₃ O₃.1.0 HCl.1.1 H₂ O: C, 50.68; H, 5.31;N, 8.44; Cl, 7.12; F, 15.27 Found: C, 50.35; H, 5.25; N, 8.52; Cl, 7.53;F, 15.43.

EXAMPLE 293S,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-pyrrolidinyl]-8-trifluoromethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

From 0.90 g (2.7 mmol) of quinolone D, 0.75 g (3.3 mmol) of pyrrolidine63, and 0.41 g (4.1 mmol) of triethylamine, there was obtained 0.88 g(60%) of the title compound. Concentration of the filtrate and washingsprovided additional product (0.42 g, 29%); mp 188°-189° C.

[α]_(D) =+224° (c=0.43, chloroform).

¹ H-NMR (CDCl₃) δ0.70-0.82 (m, 1H), 0.83-1.01 (m, 1H), 1.18-1.35 (m,2H), 1.22 (d, 3H, J=6.7 Hz), 1.46 (s, 9H), 1.64-1.84 (m, 1H), 2.07-2.19(m, 1H), 2.36-2.52 (m, 1H), 2.74 (s, 3H), 3.50-4.32 (m, 6H), 7.91 and7.93 (2×d, 1H, J=14.2 and 14.7 Hz), 8.76 (s, 1H), 14.70-14.82 (m, 1H).

Anal. Calcd. for C₂₆ H₃₁ F₄ N₃ O₅.0.30 H₂ O: C, 57.10; H, 5.82; N, 7.68;F, 13.89 Found: C, 57.38; H, 5.67; N, 7.70; F, 13.54.

3S,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-methylaminoethyl)-1-pyrrolidinyl]-8-trifluoromethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

Using Method B on 1.20 g (2.2 mmol) of the above protected quinolone,there was obtained the title compound (0.86 g); mp 218°-219° C.

¹ H-NMR (d₆ -DMSO) δ0.80-0.91 (m, 1H), 0.92-1.07 (m, 1H), 1.09-1.32 (m,2H), 1.28 (d, 3H, J=6.3 Hz), 1.65-1.73 (m, 1H), 2.02-2.21 (m, 1H),2.42-2.69 (m, 1H), 2.51 and 2.57 (2×s, 3H), 3.20-3.40 (m, 1H), 3.62-4.04(m, 5H), 7.88 (d, 1H, J=14.4 Hz), 8.77 (s, 1H), 8.80-9.10 (m, 2H), 14.90(br. s, 1H).

Anal. Calcd. for C₂₁ H₂₃ F₄ N₃ O₄.1.0 HCl.1.0 H₂ O: C, 50.86; H, 5.28;N, 8.47 Found: C, 50.51; H, 5.27; N, 8.52.

EXAMPLE 303S,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-pyrrolidinyl]-8-trifluoromethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

From 0.83 g (2.5 mmol) of quinolone D, 0.70 g (3.1 mmol) of pyrrolidine62, and 0.40 g (4.0 mmol) of triethylamine, there was obtained 0.39 g(26%) of the title compound. Concentration of the filtrate and washingsprovided additional product (0.36 g, 27%); mp 196°-197° C.

[α]_(D) =177° (c=0.44 CHCl₃).

¹ H-NMR (CDCl₃) δ0.70-0.85 (m, 1H), 0.86-1.02 (m, 1H), 1.18 (d, 3H,J=6.7 Hz), 1.23-1.37 (m, 2H), 1.48 (s, 9H), 1.70-1.91 (m, 1H), 1.93-2.10(m, 1H), 2.32-2.51 (m, 1H), 2.76 and 2.79 (2×s, 3H), 3.51-4.34 (m, 6H),7.94 (d, 1H, J=14.6 Hz), 8.79 (s, 1H), 14.70-14.80 (m, 1H).

Anal. Calcd. for C₂₆ H₃₁ F₄ N₃ O₅ : C, 57.67; H, 5.77; N, 7.76 Found: C,57.78; H, 5.92; N, 7.81.

3S,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-methylaminoethyl)-1-pyrrolidinyl]-8-trifluoromethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

Using Method B on 0.77 g (1.4 mmol) of the above protected quinolone,there was obtained the title compound (0.66 g); mp 252°-2530° C.

¹ H-NMR (d₆ -DMSO) δ0.82-0.94 (m, 1H), 0.95-1.08 (m, 1H), 1.11-1.35 (m,2H), 1.28 (d, 3H, J=6.7 Hz), 1.72-2.00 (m, 1H), 2.23-2.40 (m, 1H),2.52-2.70 (m, 1H), 2.62 (s, 3H), 3.25-3.42 (m, 1H), 3.63-4.10 (m, 5H),7.86 (d, 1H, J=14.4 Hz), 8.78 (s, 1H), 14.02 (br. s, 1H).

Anal. Calcd. for C₂₁ H₂₃ F₄ N₃ O₃.1.0 HCl.2 H₂ O: C, 49.08; H, 5.49; N,8.18 Found: C, 48.75; H, 5.60; N, 8.55.

EXAMPLE 313R,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

From 0.64 g (2.4 mmol) of quinolone B, 0.71 g (3.1 mmol) of pyrrolidine61, and 0.35 g (3.5 mmol) of triethylamine, there was obtained 0.99 g(87%) of the title compound; mp 233°-234° C.

[α]_(D) =-65° (c=0.20, chloroform).

¹ H-NMR (CDCl₃) δ1.13-1.22 (m, 5H), 1.27-1.37 (m, 2H), 1.49 (s, 9H),1.75-1.94 (m, 1H), 1.96-2.14 (m, 1H), 2.39-2.56 (m, 1H), 2.77 and 2.81(2×s, 3H), 3.32-3.43 (m, 1H), 3.45-3.82 (m, 4H), 3.97-4.30 (m, 1H), 6.81(d, 1H, J=7.4 Hz), 7.79 (d, 1H, J=14.1 Hz), 8.57 (s, 1H), 15.28-15.39(m, 1H).

Anal. Calcd. for C₂₅ H₃₂ FN₃ O₅ : C, 63.41; H, 6.81; N, 8.87; F, 4.01.Found: C, 63.30; H, 6.86; N, 9.03; F, 4.10.

3R,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-methylaminoethyl)-1-pyrrolidinyl-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

Using Method B on 1.15 g (2.4 mmol) of the above protected quinolone,there was obtained the title compound (0.35 g). Concentration of themother liquor provided additional product (0.57 g); mp >280° C.

[α]_(D) =-64° (c=1.04, 1N NaOH).

¹ H-NMR (TFA) δ1.30-1.48 (m, 2H), 1.55-1.80 (m, 5H), 2.03-2.27 (m, 1H),2.52-2.70 (m, 1H), 2.86-3.16 (m, 4H), 3.57-4.38 (m, 6H), 7.20-7.53 (m,2H), 8.13 (d, 1H, J=13.4 Hz), 9.18 (s, 1H), 11.51-11.69 (m, 1H).

Anal. Calcd. for C₂₀ H₂₄ FN₃ O₃.1.0 HCl.0.5 H₂ O: C, 57.35; H, 6.26; N,10.03 Found: C, 57.04; H, 6.02; N, 9.91.

EXAMPLE 323S,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

From 0.75 g (2.8 mmol) of quinolone B, 0.75 g (3.3 mmol) of pyrrolidine63, and 0.44 g (4.3 mmol) of triethylamine, there was obtained 1.01 g(76%) of the title compound; mp 225°-226° C.

[α]_(D) =+93° (c=0.36, chloroform).

¹ H-NMR (CDCl₃) δ1.11-1.32 (m, 7H), 1.45 and 1.48 (2×s, 9H), 1.66-1.87(m, 1H), 2.06-2.20 (m, 1H), 2.41-2.59 (m, 1H), 2.79 and 2.81 (2×s, 3H),3.28-3.82 (m, 5H), 3.99-4.32 (m, 1H), 6.77 (d, 1H, J=7.0 Hz), 7.77 (d,1H, J=14.1 Hz), 8.55 (s, 1H), 15.32-15.38 (m, 1H).

Anal. Calcd. for C₂₅ H₃₂ FN₃ O₅.0.20 H₂ O: C, 62.93; H, 6.84; N, 8.81Found: C, 62.99; H, 6.81; N, 8.59.

3S,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-methylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

Using Method C on 1.09 g (2.3 mmol) of the above protected quinoloneafforded the title compound (0.83 g); mp >280° C.

[α]_(D) =55° (c=1.03, 1N NaOH).

¹ H-NMR (d₆ -DMSO+TFA) δ1.42-1.51 (m, 2H), 1.53-1.79 (m, 5H), 2.05-2.25(m, 1H), 2.41-2.54 (m, 1H), 2.80-3.00 (m, 1H), 2.95 (s, 3H), 3.60-3.74(m, 1H), 3.76-4.29 (m, 5H), 7.38 (d, 1H, J=7.3 Hz), 8.11 (d, 1H, J=14.0Hz), 8.90 (s, 1H).

Anal. Calcd. for C₂₀ H₂₄ FN₃ O₃.1.0 HCl.0.8 H₂ O: C, 56.62; H, 6.32; N,9.90; Cl, 8.36 Found: C, 56.92; H, 6.22; N, 9.89; Cl, 8.39.

EXAMPLE 333S,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

From 0.66 g (2.5 mmol) of quinolone B, 0.70 g (3.1 mmol) of pyrrolidine62, and 0.40 g (4.0 mmol) of triethylamine, there was obtained 1.08 g(91%) of the title compound; mp 223.5°-224.5° C.

[α]_(D) =69° (c=0.81, chloroform).

¹ H-NMR (CDCl₃) δ1.12-1.24 (m, 5H), 1.29-1.37 (m, 2H), 1.49 (s, 9H),1.78-1.93 (m, 1H), 1.97-2.15 (m, 1H), 2.39-2.56 (m, 1H), 2.77 and 2.81(2×s, 3H), 3.30-3.41 (m, 1H), 3.42-3.80 (m, 4H), 3.96-4.31 (m, 1H), 6.83(d, 1H, J=7.4 Hz), 7.83 (d, 1H, J=14.1 Hz), 8.60 (s, 1H), 15.30-15.38(m, 1H).

Anal. Calcd. for C₂₅ H₃₂ FN₃ O₅ : C, 63.41; H, 6.81; N, 8.87 Found: C,63.60; H, 7.12; N, 8.92.

3S,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-methylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

Using Method B on 1.10 g (2.3 mmol) of the above protected quinolone,there was obtained the title compound (0.61 g). Concentration of themother liquor provided additional product (0.22 g); mp >280° C.

[α]_(D) =72° (c=0.52, 1N NaOH).

¹ H-NMR (d₆ -DMSO+TFA) δ1.12-1.20 (m, 2H), 1.22-1.38 (m, 2H), 1.30 (d,3H, J=6.6 Hz), 1.79-1.96 (m, 1H), 2.20-2.37 (m, 1H), 2.50-2.68 (m, 1H),2.64 (s, 3H), 3.27-3.52 (m, 2H), 3.58-3.85 (m, 4H), 7.11 (d, 1H, J=7.4Hz), 7.84 (d, 1H, J=14.2 Hz), 8.61 (s, 1H), 15.50 (s, 1H).

Anal. Calcd. for C₂₀ H₂₄ FN₃ O₃.1.0 HCl.0.4 H₂ O: C, 57.59; H, 6.23; N,10.07; Cl, 8.50 Found: C, 57.68; H, 6.10; N, 10.07; Cl, 8.54.

EXAMPLE 343S,1R-1-cyclopropyl-5-amino-6,8-difluoro-7-[3-(1-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

From 0.81 g (2.7 mmol) of quinolone L, 0.75 g (3.3 mmol) of pyrrolidine63, and 0.44 g (4.3 mmol) of triethylamine, there was obtained 0.62 g(45%) of the title compound. Concentration of the filtrate and washingsprovided additional product (0.50 g, 37%); mp 198°-199° C.

[α]_(D) =+230° (c=0.45, chloroform).

¹ H-NMR (CDCl₃) δ0.98-1.25 (m, 7H), 1.46 (s, 9H), 1.60-1.75 (m, 1H),1.98-2.12 (m, 1H), 2.27-2.44 (m, 1H), 2.76 (d, 3H, J=7.1 Hz), 3.48-3.79(m, 5H), 3.82-4.30 (m, 1H), 6.30-6.45 (m, 2H), 8.57 (s, 1H), 14.92 and14.95 (2×s, 1H).

Anal. Calcd. for C₂₅ H₃₂ F₂ N₄ O₅.0.4 H₂ O: C, 58.45; H, 6.44; N, 10.91Found: C, 58.46; H, 6.17.; N, 10.88.

3S,1R-5-amino-1-cyclopropyl-6,8-difluoro-7-[3-(1-N-methylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

Using 1.58 g (3.1 mmol) of the above quinolone, hydrolysis of thetert-butoxycarbonyl group with hydrogen chloride in methylene chloride,followed by 6N HCl, provided the title compound (0.14 g) as thehydrochloride salt.

¹ H-NMR (TFA) δ1.25-1.55 (m, 4H), 1.57-1.70 (m, 3H), 1.92-2.11 (m, 1H),2.30-2.51 (m, 1H), 2.70-2.88 (m, 1H), 2.93-3.10 (m, 3H), 3.58-3.72 (m,1H), 3.80-4.20 (m, 5H), 7.10-7.60 (m, 2H), 9.14 (s, 1H).

EXAMPLE 353S,1S-5-amino-1-cyclopropyl-6,8-difluoro-7-[3-(1-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

From 0.78 g (2.6 mmol) of quinolone L, 0.71 g (3.1 mmol) of pyrrolidine62, and 0.51 g (5.0 mmol) of triethylamine, there was obtained 1.06 g(80%) of the title compound. Concentration of the filtrate and washingsprovided additional product (0.21 g, 16%); mp 207.5°-208.5° C.

[α]_(D) =198° (c=0.42, CHCl₃).

¹ H-NMR (CDCl₃) δ0.98-1.25 (m, 7H), 1.48 (s, 9H), 1.62-1.82 (m, 1H),1.84-2.04 (m, 1H), 2.27-2.41 (m, 1H), 2.76 and 2.79 (2×s, 3H), 3.45-3.60(m, 1H), 3.61-3.95 (m, 4H), 3.96-4.31 (m, 1H), 6.30-6.48 (m, 2H), 8.58(s, 1H), 14.90 and 14.93 (2×s, 1H).

Anal. Calcd. for C₂₅ H₃₂ F₂ N₄ O₅ : C, 59.28; H, 6.37; N, 11.06; F, 7.50Found: C, 59.46; H, 6.54; N, 11.08; F, 6.99.

3S,1S-5-amino-1-cyclopropyl-6,8-difluoro-7-[3-(1-N-methylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

Using 0.75 g (1.8 mmol) of the above quinolone, hydrolysis of thetert-butoxycarbonyl group with hydrogen chloride in methylene chloride,followed by 6N HCl, provided the title compound (0.58 g) as thehydrochloride salt; mp >250° C.

¹ H-NMR (TFA) δ1.26-1.60 (m, 4H), 1.61 (d, 3H, J=6.2 Hz), 1.96-2.12 (m,1H), 2.45-2.60 (m, 1H), 2.72-2.89 (m, 1H), 3.04 (s, 3H), 3.53-3.69 (m,1H), 3.91-4.40 (m, 5H), 7.20-7.40 (m, 1H), 9.16 (s, 1H).

Anal. Calcd. for C₂₀ H₂₄ F₂ N₄ O₃.2.0HCl.0.60H₂ O: C, 49.01; H, 5.59; N,11.43. Found: C, 49.09; H, 5.55; N, 1.07.

General Procedure for 8-Methoxy Quinolone Carboxylic Acids

These derivatives were obtained by reaction of the appropriatepyrrolidine side chain (2 eq) with the7-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid borateester according to the general procedure, except that no triethylaminewas added to the reaction mixture. The resulting ester was subsequentlyhydrolyzed with triethylamine in 80% aqueous ethanol.

EXAMPLE 363R,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-pyrrolidinyl]-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid borate ester

From 0.90 g (2.6 mmol) of 8-methoxyquinolone borate ester, and 0.65 g(2.6 mmol) of pyrrolidine 60, there was obtained 1.00 g (70%) of thetitle compound.

¹ H-NMR (CDCl₃) δ0.80-0.92 (m, 1H), 0.93-1.08 (m, 1H), 1.10-1.29 (m,5H), 1.46 (s, 9H), 1.61-1.80 (m, 1H), 2.05-2.20 (m, 1H), 2.32-2.49 (m,1H), 2.75 and 2.78 (2×s, 3H), 3.62 (s, 3H), 3.65-3.81 (m, 2H), 3.82-4.14(m, 2H), 4.20-4.38 (m, 2H), 7.82 (br. d, 1H, J=13.8 Hz), 8.93 (s, 1H).

3R,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-pyrrolidinyl]-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

From 0.80 g (1.5 mmol) of the above borate ester and (3.6 mmol) oftriethylamine in 20 mL of 80% aqueous ethanol, there was obtained 0.56 g(74%) of the title compound after recrystallization fromdichloromethane/heptane.

¹ H-NMR (CDCl₃) δ0.80-0.98 (m, 1H), 1.03-1.40 (m, 6H), 1.44 (s, 9H),1.52-1.88 (m, 1H), 1.98-2.20 (m, 1H), 2.31-2.50 (m, 1H), 2.73 and 2.75(2×s, 3H), 3.30-3.60 (m, 2H), 3.55 (s, 3H), 3.62-4.40 (m, 4H), 7.80 (br.d, 1H), 8.74 (s, 1H), 15.02-15.10 (m, 1H).

3R,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-methylaminoethyl)-1-pyrrolidinyl]-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

Using Method A on 0.75 g (1.5 mmol) of the above protected quinolone,there was obtained the title compound (0.40 g) as a yellow solid; mp166°-167° C.

[α]_(D) =-105° (c=1.08, methanol).

¹ H-NMR (d₆ -DMSO+CD₃ OD) δ0.87-0.99 (m, 1H), 1.01-1.27 (m, 3H), 1.32(d, 3H, J=6.0 Hz), 1.70-1.90 (m, 1H), 2.08-2.11 (m, 1H), 2.49-2.73 (m,4H), 3.48-3.69 (m, 3H), 3.57 (s, 3H), 3.71-3.82 (m, 2H), 4.08-4.20 (m,1H), 7.65 (d, 1H, J=13.8 Hz), 8.66 (s, 1H), 9.09-9.29 (m, 1H), 9.31-9.55(m, 1H), 15.10-15.20 (br. s, 1H).

Anal. Calcd. for C₂₁ H₂₆ FN₃ O₄.1.0 HCl.1.4 H₂ O: C, 54.23; H, 6.46; N,9.03: Cl, 7.62 Found: C, 54.04; H, 6.30; N, 8.99; Cl, 8.11.

EXAMPLE 373R,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-tert-butoxycarbonyl)-1-pyrrolidinyl]-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid borate ester

From 0.90 g (2.6 mmol) of 8-methoxyquinolone borate ester, and 1.16 g(5.1 mmol) of pyrrolidine 61, there was obtained 1.41 g (98%) of thetitle compound after recrystallization from dichloromethane/ether.

¹ H-NMR (CDCl₃) δ0.98-1.08 (m, 1H), 1.12-1.30 (m, 6H), 1.48 (s, 9H),1.70-1.87 (m, 1H), 1.92-2.13 (m, 1H), 2.32-2.52 (m, 1H), 2.79 and 2.82(2×s, 3H), 3.55-4.20 (m, 6H), 3.64 (s, 3H), 7.77 (d, 1H, J=13.7 Hz),8.90 (s, 1H).

Anal. Calcd. for C₂₆ H₃₃ BF₃ N₃ O₆ : C, 56.64; H, 6.03; N, 7.62 Found:C, 56.68; H, 6.16; N, 7.55.

3R,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-tert-butoxycarbonyl)-1-pyrrolidinyl]-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

From 1.35 g (2.5 mmol) of borate ester and 2.50 g (25 mmol) oftriethylamine in 60 mL of 80% aqueous ethanol, there was obtained 0.63 g(50%) of the title compound after recrystallization fromdichloromethane/hexane. Concentration of the mother liquor providedadditional product (0.50 g, 40%); mp 140°-145° C.

[α]_(D) =-116° (c=1.06, chloroform).

¹ H-NMR (CDCl₃) δ0.85-0.97 (m, 1H), 1.02-1.30 (m, 3H), 1.18 (d, 3H,J=6.6 Hz), 1.49 (s, 9H), 1.65-1.88 (m, 1H), 1.91-2.10 (m, 1H), 2.29-2.43(m, 1H), 2.78 and 2.81 (2×s, 3H), 3.45-3.65 (m, 3H), 3.57 (s, 3H),3.72-3.83 (m, 1H), 3.96-4.36 (m, 2H), 7.76 (d, 1H, J=13.8 Hz), 8.77 (s,1H), 14.95-15.20 (m, 1H).

Anal. Calcd. for C₂₆ H₃₄ FN₃ O₆.1.6 H₂ O: C, 58.66; H, 7.04; N, 7.89Found: C, 58.62; H, 7.02; N, 8.09.

3R,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-methylaminoethyl)-1-pyrrolidinyl]-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

Using Method A on 1.20 g (2.4 mmol) of the above protected quinolone,there was obtained the title compound (0.46 g); mp 212°-213° C. (dec.).

[α]_(D) =-165° (c=1.01, 1N NaOH).

¹ H-NMR (d₆ -DMSO) δ0.86-1.25 (m, 4H), 1.27 (d, 3H, J=6.5 Hz), 1.71-1.92(m, 1H), 2.20-2.33 (m, 1H), 2.47-2.62 (m, 1H), 2.57 (s, 3H), 3.50-3.65(m, 3H), 3.57 (s, 3H), 3.70-3.80 (m, 2H), 4.10-4.19 (m, 1H), 7.66 (d,1H, J=13.9 Hz), 8.66 (s, 1H), 8.90-9.20 (m, 2H), 15.00-15.15 (m, 1H).

Anal. Calcd. for C₂₁ H₂₆ FN₃ O₄.1.0 HCl.2.0 H₂ O: C, 53.00; H, 6.57; N,8.83; Cl, 7.45 Found: C, 52.69; H, 6.47; N, 8.72; Cl, 7.44.

EXAMPLE 383S,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-pyrrolidinyl]-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid borate ester

From 0.86 g (2.5 mmol) of 8-methoxyquinolone borate ester, and 1.14 g(5.0 mmol) of pyrrolidine 63, there was obtained 1.34 g (97%) of thetitle compound after recrystallization from dichloromethane/ether; mp185°-186° C.

[α]_(D) =+87° (c=0.56, chloroform).

¹ H-NMR (CDCl₃) δ0.94-1.07 (m, 1H), 1.16-1.29 (m, 2H), 1.24 (d, 3H,J=6.8 Hz), 1.31-1.50 (m, 1H), 1.47 (s, 9H), 1.60-1.82 (m, 1H), 2.06-2.10(m, 1H), 2.32-2.51 (m, 1H), 2.75 and 2.78 (2×s, 3H), 3.43-3.85 (m, 3H),3.62 (s, 3H), 3.87-4.38 (m, 3H), 7.82 (br. d, 1H, J=13.8 Hz), 8.92 (s,1H).

Anal. Calcd. for C₂₆ H₃₃ BF₃ N₃ O₆ : C, 56.64; H, 6.03; N, 7.62 Found:C, 56.61; H, 6.00; N, 7.28.

3S,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-t-butoxycarbonyl-N-methylaminoethyl)-1-pyrrolidinyl]-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

From 1.35 g (2.5 mmol) of borate ester and 2.50 g (25 mmol) oftriethylamine in 50 mL of 80% aqueous ethanol, there was obtained 1.17 g(93%) of the title compound.

¹ H-NMR (CDCl₃) δ0.82-0.95 (m, 1H), 1.01-1.12 (m, 2H), 1.17-1.29 (m,4H), 1.46 (s, 9H), 1.60-1.77 (m, 1H), 2.02-2.16 (m, 1H), 2.29-2.48 (m,1H), 2.74 and 2.77 (2×s, 3H), 3.38-3.70 (m, 3H), 3.56 (s, 3H), 3.79-3.90(m, 1H), 3.91-4.33 (m, 2H), 7.78 (d, 1H, J=13.9 Hz), 8.77 (s, 1H).

3S,1R-1-cyclopropyl-6-fluoro-7-[3-(1-N-methylaminoethyl)-1-pyrrolidinyl]-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxyacid

Using Method A on 1.10 g (2.2 mmol) of the above protected quinolone,there was obtained the title compound (0.57 g). Concentration of themother liquor provided additional product (0.22 g); mp 190°-195° C.

¹ H-NMR (d₆ -DMSO) δ1.06-1.23 (m, 4H), 1.31 (d, 3H, J=6.3 Hz), 1.69-1.87(m, 1H), 2.04-2.10 (m, 1H), 2.48-2.64 (m, 1H), 2.55 (s, 3H), 3.00-3.12(m, 1H), 3.45-3.65 (m, 2H), 3.57 (s, 3H), 3.66-3.80 (m, 2H), 4.08 -4.19(m, 1H), 7.66 (d, 1H, J=13.8 Hz), 8.66 (s, 1H), 8.91-9.10 (m, 1H),9.13-9.31 (m, 1H), 15.10-15.20 (m, 1H).

Anal. Calcd. for C₂₁ H₂₆ FN₃ O₄.1.0 HCl.2.0 H₂ O: C, 53.00; H, 6.57; N,8.83 Found: C, 52.76; H, 6.43; N, 8.71.

EXAMPLE 393S,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-pyrrolidinyl]-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid borate ester

From 0.86 g (2.5 mmol) of 8-methoxyquinolone borate ester, and 1.15 g(5.0 mmol) of pyrrolidine 62, there was obtained 1.04 g (75%) of thetitle compound after recrystallization from dichloromethane/ether; mp189°-190° C.

[α]_(D) =105° (c=0.34, chloroform).

¹ H-NMR (CDCl₃) δ0.98-1.06 (m, 1H), 1.10-1.32 (m, 6H), 1.49 (s, 9H),1.72-1.90 (m, 1H), 1.93-2.14 (m, 1H), 2.30-2.48 (m, 1H), 2.78 and 2.82(2×s, 3H), 3.56-4.37 (m, 6H), 3.62 (s, 3H), 7.85 (d, 1H, J=13.7 Hz),8.94 (s, 1H).

Anal. Calcd. for C₂₆ H₃₃ BF₃ N₃ O₆.0.5 H₂ O: C, 55.73; H, 6.12; N, 7.50Found: C, 55.61; H, 6.24; N, 7.49.

3S,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-pyrrolidinyl]-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

From 1.00 g (1.8 mmol) of borate ester and 2.50 g (25 mmol) oftriethylamine in 50 mL of 80% aqueous ethanol, there was obtained 0.85 g(93%) of the title compound.

¹ H-NMR (CDCl₃) δ0.85-0.95 (m, 1H), 1.03-1.30 (m, 3H), 1.18 (d, 3H,J=6.8 Hz), 1.49 (s, 9H), 1.68-1.89 (m, 1H), 1.91-2.10 (m, 1H), 2.28-2.44(m, 1H), 2.77 and 2.81 (2×s, 3H), 3.45-3.64 (m, 3H), 3.57 (s, 3H),3.70-3.87 (m, 1H), 3.94-4.08 (m, 1H), 4.16-4.36 (m, 1H), 7.77 (d, 1H,J=13.8 Hz), 8.77 (s, 1H).

3S,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-methylaminoethyl)-1-pyrrodinyl]-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

Using Method A on 1.24 g (2.5 mmol) of the above protected quinolone,there was obtained the title compound (0.18 g). Concentration of themother liquor provided additional product (0.03 g); mp 173°-174° C.(dec).

¹ H-NMR (d₆ -DMSO+TFA) δ0.85-1.25 (m, 4H), 1.26 (d, 3H, J=6.2 Hz),1.72-1.90 (m, 1H), 2.15-2.31 (m, 1H), 2.42-2.60 (m, 1H), 2.63 (s, 3H),3.25-3.43 (m, 1H), 3.45-3.68 (m, 6H), 3.70-3.88 (m, 1H), 4.09-4.20 (m,1H), 7.64 (d, 1H, J=13.8 Hz), 8.52-8.80 (m, 2H), 12.10-12.60 (m, 1H).

EXAMPLE 403R,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-methylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

This compound was prepared by reacting a suspension of the quinolone B(0.80 g, 3.0 mmol) and triethylamine (0.33 g, 3.3 mmol) in acetonitrile(15 mL) with the unprotected side chain 64 (0.42 g, 3.3 mmol) accordingto the general coupling procedure. The title compound (0.60 g) wasobtained. Concentration of the filtrate and washings provided additionalproduct (0.43 g); mp 229°-230° C.

¹ H-NMR (TFA) δ1.35-1.42 (m, 2H), 1.55-1.70 (m, 2H), 1.64 (d, 3H, J=6.4Hz), 2.05-2.19 (m, 1H), 2.41-2.58 (m, 1H), 2.82-3.18 (m, 1H), 3.04 (br.s, 3H), 3.59-3.77 (m, 1H), 3.81-4.06 (m, 4H), 4.32-4.42 (m, 1H),7.10-7.40 (m, 1H), 7.35 (d, 1H, J=6.8 Hz), 8.13 (d, 1H, J=13.5 Hz), 9.18(s, 1H), 11.63 (br. s, 1H).

Anal. Calcd. for C₂₀ H₂₄ FN₃ O₃.2.0 HF.0.5 H₂ O: C, 56.86; H, 6.44; N,9.95 Found: C, 56.68; H, 6.11; N, 9.98.

EXAMPLE 413R,1R-5-amino-1-cyclopropyl-6,8-difluoro-7-[3-(1-N-methylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

This compound was prepared by reacting a suspension of the quinolone L(1.19 g, 4.0 mmol) and triethylamine (0.71 g, 5.5 mmol) in acetonitrile(50 mL) with the unprotected side chain 65 (0.70 g, 5.5 mmol) accordingto the general coupling procedure. The title compound (1.62 g) wasobtained; mp 198°-199° C.

¹ H-NMR (TFA) δ1.25-1.70 (m, 4H), 1.61 (d, 3H, J=6.6 Hz), 1.93-2.10 (m,1H), 2.43-2.60 (m, 1H), 2.70-2.88 (m, 1H), 3.06 and 3.07 (2×s, 3H),3.53-3.70 (m, 1H), 3.85-4.00 (m, 1H), 4.01-4.40 (m, 4H), 7.05-7.35 (m,1H), 9.14 (s, 1H).

Anal. Calcd. for C₂₀ H₂₄ F₂ N₄ O₃.1.5 H₂ O: C, 55.42; H, 6.28; N, 12.93Found: C, 55.70; H, 6.14; N, 12.86.

EXAMPLE 423R,1S-5-amino-1-cyclopropyl-6,8-difluoro-7-[3-(1-N-methylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

This compound was prepared by reacting a suspension of the quinolone L(0.89 g, 3.0 mmol) and triethylamine (0.46 g, 4.5 mmol) in acetonitrile(30 mL) with the unprotected side chain 64 (0.57 g, 4.4 mmol) accordingto the general coupling procedure. The title compound (0.59 g) wasobtained;

[α]_(D) =-210° (c=0.46, 1N NaOH).

¹ H-NMR (TFA) δ1.22-1.39 (m, 2H), 1.40-1.55 (m, 2H), 1.64 (d, 3H, J=6.6Hz), 1.85-2.07 (m, 1H), 2.35-2.50 (m, 1H), 2.68-2.86 (m, 1H), 3.01 and3.03 (2×s, 3H), 3.55-3.70 (m, 1H), 3.96-4.20 (m, 5H), 7.03-7.42 (m, 1H),9.13 (s, 1H), 11.58 (s, 1H).

Anal. Calcd. for C₂₀ H₂₄ F₂ N₄ O₃.1.5 HF.0.7 H₂ O: C, 53.50; H, 6.04; N,12.48; F, 14.81 Found: C, 53.56; H, 5.77; N, 12.51; F, 14.96.

EXAMPLE 433R,1S-7-[3(1-aminoethyl)-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid

A mixture of7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid G (0.05 g, 1.52 mmol), pyrrolidine 20 (0.32 g, 1.52 mmol), Et₃ N (1mL, 7.18 mmol) in CH₃ CN (20 mL) was refluxed for 18 hours. The solutionwas cooled and concentrated. The residue was dissolved in CH₂ Cl₂ (50mL), cooled to 0° C. and treated with gaseous HCl. The reaction wasallowed to stir at room temperature for 18 hours and then concentrated.The residue was suspended in H₂ O (10 mL) and 1N NaOH was added untilthe pH of the solution was 12. The mixture was filtered and the filtrateacidified with HCl to pH 7.1. The resulting solid was filtered, washedwith water and dried to provide the title compound in a yield of 74%; mp140°-145° C.

EXAMPLE 443R,1S-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid

A solution of 0.53 g (1.55 mmol) of1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid-borondifluoride complex, 0.40 (1.87 mmol) of pyrrolidine 20, 0.60 g(4.6 mmol) of diisopropyiethylamine, and 25 mL of acetonitrile wasstirred for 3 days at room temperature. The solution was concentrated toan orange oil which was dissolved in 95% ethanol (20 mL) and treatedwith 5 mL of triethylamine. The solution was heated at reflux for 2hours, then cooled to room temperature and concentrated. The solid thatwas obtained was chromatographed (silica gel, 230-400 mesh), elutingwith CHCl₃ /MeOH (9/1), to give 0.69 g of3R,1S-7-[3-(1-t-butoxycarbonylaminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid as a foam, mp 145°-147° C.

The above compound (0.69 g, 1.4 mmol) was dissolved in 30 mL ofchloroform, cooled to 5° C., and treated with a steady stream of gaseousHCl for 15 minutes. The solution was allowed to warm to room temperatureand concentrated in vacuo. The residue was triturated with2-propanol:ethyl acetate (1:10), and the solids were filtered, washedwith ether, and dried to give 0.54 g of the title compound as thehydrochloride salt; mp 236°-238° C.

Anal. Calcd. for C₂₀ H₂₄ FN₃ O₄.125 HCl.H₂ O: C, 50.04; H, 6.35; N,8.75; Cl, 9.23. Found: C, 50.09; H, 5.97; N, 8.82; Cl, 9.44.

HPLC: 99.5%

¹ H-NMR (TFA) δ9.41 (s, 1H), 8.18 (d, 1H), 4.55 (m, 1H), 4.32 (m, 2H),4.14 (m, 2H), 3.93 (bs, 4H), 2.57 (m, 1H), 3.09 (m, 1H), 2.21 (m, 1H),1.69 (d, J=5.5 Hz, 3H), 1.61 (m, 1H), 1.50 (m, 1H), 1.33 (m, 1H), 1.21(m, 1H).

EXAMPLE 453R,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid

The procedure above was used to prepare the title compound (0.54 g) from0.58 g (1.7 mmol) of1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid-borondifluoride complex and 0.43 g (2.0 mmol) of 21. The titlecompound was isolated as the hydrochloride salt; mp 215°-218° C.

Anal. Calcd. for C₂₀ H₂₄ FN₃ O₄.1.15 HCl.2.1 H₂ O: C, 51.20; H, 6.30; N,8.95; Cl, 8.69. Found: C, 51.20; H, 6.00; N, 8.68; Cl, 8.36.

¹ H-NMR (DMSO-d₆) δ8.66 (s, 1H), 8.30 (bs, 2H), 7.66 (d, J=14 Hz, 1H),4.14 (m, 1H), 3.77 (m, 1H), 3.56 (bs, 6H), 3.26 (m, 1H), 2.45 (m, 1H,2.21 (m, 1H), 1.78 (m, 1H), 1.26 (d, J=6 Hz, 3H), 1.17-0.98 (m, 4H).

EXAMPLE 463R,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid

A solution of 0.40 g (1.4 mmol) of1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid J, 0.30 g (1.4 mmol) of pyrrolidine 21, 0.36 g (3.6 mmol) oftriethylamine, and 20 mL of acetonitrile was heated at reflux for 4hours. The solution was cooled to 5° C., and the solids were filtered.The product was washed with water and ether, dried, and dissolved in 30mL of chloroform. This solution was cooled to 5° C. and treated with asteady stream of gaseous HCl for 10 minutes. The mixture was allowed towarm to room temperature, stirred for 18 hours, and filtered. The solidswere collected via filtration, washed with ether, and dried in vacuo togive 0.46 g of the title compound as the hydrochloride salt; mp >300° C.

Anal. Calcd. for C₂₃ H₂₂ F₃ N₃ O₃.HCl.2.5 H₂ O: C, 52.42; H, 5.36; N,7.97; Cl, 6.72. Found: C, 52.24; H, 4.99; N, 7.80; Cl, 6.68.

¹ H-NMR (DMSO-d₆) δ8.67 (s, 1H), 8.15 (bs, 2H), 7.9 (m, 1H), 7.7 (m,1H), 7.4 (m, 1H), 5.7 (d, 1H), 3.6-3.15 (m, 5H), 2.78 (d, 3H), 2.4 (m,1H), 2.15 (m, 1H), 1.7 (m, 1H), 1.17 (d, 3H).

EXAMPLE 473R,1S-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid

A solution of 0.38 g (1.4 mmol) of1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid I, 0.32 g (1.5 mmol) of pyrrolidine 20, 0.42 g (4.2 mmol) oftriethylamine, and 25 mL of acetonitrile was heated at reflux for 4hours, then cooled to 5° C. The mixture was diluted with ether, and thesolids were filtered, washed with ether, and dried to give3R,1S-7-[3-(1-t-butoxycarbonylaminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid, mp 188°-191° C.

The above compound was dissolved in 30 mL of chloroform, cooled to 5°C., and treated with a steady stream of gaseous HCl for 10 minutes. Thesolution was allowed to warm to room temperature overnight. Ether wasadded and the solids were filtered, washed with ether, and dried to give0.43 g of the title compound as the hydrochloride salt; mp 266°-268° C.

Anal. Calcd. for C₂₀ H₂₄ FN₃ O₃.1.1 HCl.1.2 H₂ O: C, 55.20; H, 6.37; N,9.66; Cl, 8.96. Found: C, 55.14; H, 6.08; N, 9.54; Cl, 8.91.

H¹ -NMR (DMSO-d₆ +TFA) δ8.55 (s, 1H), 7.02 (d, J=7 Hz, 1H), 3.72 (m,4H), 3.48 (m, 1H), 3.35 (m, 1H), 2.74 (d, 3H), 2.47 (m, 1H), 2.15 (m,1H), 1.79 (m, 1H), 1.37 (m, 2H), 1.30 (d, J=6.5 Hz, 3H), 1.11 (m, 2H).

EXAMPLE 483R,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid

A solution of 0.40 g (1.1 mmol) of7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid G, 0.30 g (1.4 mmol) of pyrrolidine 21, 0.36 g (3.6 mmol) oftriethylamine, and 15 mL of acetonitrile was heated at reflux for 5hours. The suspension was cooled to 5° C., and the solids were filtered,washed with water and ether, and dried to give 0.48 g of3R,1R-7-[3-(1-N-t-butoxycarbonylaminoethyl)-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid.

The above compound was dissolved in 20 mL of chloroform, cooled to 5°C., and treated with a steady stream of gaseous HCl for 10 minutes. Thesolution was warmed to room temperature and concentrated by half. Etherwas added, and the solids that formed were filtered, washed with ether,and dried to give 0.38 g of the title compound as the hydrochloridesalt; mp 265°-268° C.

Anal. Calcd. for C₂₁ H₁₉ F₃ N₄ O₃.1.1 HCl.1.2 H₂ O: C, 51.04; H, 4.59;N, 11.34; Cl, 7.89. Found: C, 50.93; H, 4.45; N, 11.22; Cl, 7.62.

¹ H-NMR (DMSO-d₆) δ15.16 (bs, 1H), 8.83 (s, 1H), 8.20 (bs, 2H), 8.05 (d,J=12 Hz, 1H), 7.80 (m, 1H), 7.61 (m, 1H), 7.34 (m, 1H), 3.35 (m, 5H),2.33 (m, 1H), 2.12 (m, 1H), 1.68 (m, 1H), 1.15 (bs, 3H).

EXAMPLE 493R,1S-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-8-ethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

A solution of 0.55 g (1.55 mmole) of1-cyclopropyl-8-ethoxy-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid borondifluoride complex, 0.40 g (1.9 mmol) of pyrrolidine 20, 0.60g (4.6 mmol) of diisopropyiethylamine, and 25 mL of acetonitrile wasstirred at room temperature for 3 days. The solution was concentrated toa yellow foam which was dissolved in 20 mL of ethanol, treated with 5 mLof triethylamine, and heated at reflux for 5 hours. The mixture wasconcentrated to a gold solid which was chromatographed (silica gel,eluting with 90:10 CHCl₃ :MeOH) to give 0.76 g of3R,1S-7-[3-(1-N-t-butoxycarbonylaminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-8-ethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, mp 161°-163° C.

The above compound (0.74 g, 1.5 mmol) was dissolved in 30 mL ofchloroform, cooled to 5° C., and treated with a steady stream of gaseousHCl for 10 minutes. The solution was allowed to warm to room temperatureand stirred for 90 minutes. The suspension was concentrated, and theresidue was triturated with ethyl acetate. The solids were filtered,washed with ethyl acetate, and dried to give 0.56 g of the titlecompound as the hydrochloride salt; mp 222°-224° C.

Anal. Calcd. for C₂₁ H₂₆ FN₃ O₄.1.25 HCl.2.5 H₂ O: C, 51.05; H, 6.58; N,8.50; Cl, 8.97. Found: C, 51.14; H, 6.35; N, 8.49; Cl, 8.42.

¹ H-NMR (DMSO-d₆) δ15.15 (s, 1H), 8.67 (s, 1H), 8.22 (bs, 3H), 7.66 (d,J=14.0 Hz, 1H), 4.14 (m, 1H), 3.72 (m, 4H), 3.48 (m, 2H), 3.28 (m, 1H),2.41 (m, 1H), 2.10 (m, 1H), 1.72 (m, 1H), 1.30 (m, 7H), 1.06 (m, 2H),0.90 (m, 1H).

EXAMPLE 503R,1S-7-[3-(1-N-ethylaminoethyl)-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid

A solution of 0.71 g (2.0 mmol) of7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid G, 0.31 g (2.2 mmol) of pyrrolidine 44, 0.61 g (6.0 mmol) oftriethylamine, and 15 mL of acetonitrile was heated at reflux for 3hours, then cooled to room temperature and concentrated. The residue wasdissolved in water which was basified to pH 11 with 10% NaOH, filteredthrough a fiberglass pad, and neutralized to pH 7.2. The solids thatformed were filtered, washed with ether, and dried in vacuo to give 0.65g of the title compound; mp 136°-138° C.

Anal. Calcd. for C₂₃ H₂₃ F₃ N₄ O₃.2H₂ O: C, 55.64; H, 5.48; N, 11.28.Found: C, 55.42; H, 5.22; N, 11.31.

¹ H-NMR (DMSO-d₆) δ8.78 (s, 1H), 8.00 (d, J=13 Hz, 1H), 7.80 (q, 1H),7.56 (5, 1H), 7.32 (m, 1H), 4.0-3.3 (m, 4H), 2.61 (m, 1H), 2.39 (m, 2H),2.02 (m, 2H), 1.55 (m, 1H), 0.98 (m, 6H).

EXAMPLE 513R,1R-7-[3-(1-N-ethylaminoethyl)-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid

The procedure outlined in Example 50 was used to prepare the titlecompound (0.71 g) from 0.71 g (2.0 mmol) of7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid G, 0.31 g (2.2 mmol) of pyrrolidine 45, and 0.61 g (6.0 mmol) oftriethylamine. The title compound was isolated via isoelectricprecipitation at pH 7.2, mp 203°-205° C.

EXAMPLE 523R,1S-1-cyclopropyl-7-[3-(1-N-ethylaminoethyl)-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid

A solution of 0.56 g (2.0 mmole) of1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid I, 0.31 g (2.2 mmol) of pyrrolidine 44, 0.61 g (6.0 mmol) oftriethylamine, and 15 mL of acetonitrile was heated at reflux for 4hours. The solution was cooled and concentrated to an orange solid. Theresidue was dissolved in water, filtered through a fiberglass pad,acidified to pH 2.0, and lyophilized. The yellow powder was dissolved inconcentrated hydrochloric acid and filtered; the filtrate wasconcentrated to a gold oil which was triturated with 2-propanol:ether(1:1). The solids were filtered, washed with 2-propanol and ether, anddried in vacuo to give 0.41 g of the title compound as the hydrochloridesalt; mp >300° C.

Anal. Calcd. for C₂₂ H₂₈ FN₃ O₃.1.4 HCl.1H₂ O: C, 56.16; H, 6.73; N,8.93; Cl, 10.55. Found: C, 56.19; H, 6.45; N, 8.99; Cl, 10.38.

¹ H-NMR (DMSO-d₆) δ8.55 (s, 1H), 7.06 (d, J=2 Hz, 1H), 3.87 (m, 1H),3.67 (m, 3H), 3.45 (m, 1H), 3.04 (m, 2H), 2.73 (d, J=3 Hz, 3H), 2.55 (m,2H), 2.16 (m, 1H), 1.82 (m, 1H), 1.40 (m, 2H), 1.28 (m, 6H), 1.09 (m,2H).

EXAMPLE 533R,1S-5-amino-1-cyclopropyl-7-[3-(1-N-ethylaminoethyl)-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

A solution of 0.60 g (2.0 mmol) of5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid L, 0.31 g (2.2 mmol) of pyrrolidine 44, 0.61 g (6.0 mmol) oftriethylamine, and 20 mL of acetonitrile was heated at reflux for 5hours. The solution was cooled to room temperature and concentrated. Theresidue was taken up in water which was basified to pH 11, filteredthrough a fiberglass pad, and neutralized to pH 7.8. The solids thatformed were filtered, washed with water and ether, and dried to give0.61 g of the title compound; mp 148°-150° C.

Anal. Calcd. for C₂₁ H₂₆ F₂ N₄ O₃.0.5H₂ O: C, 58.73; H, 6.34; N, 13.05.Found: C, 58.59; H, 6.41; N, 13.45.

¹ H-NMR (DMSO-d₆) δ8.41 (s, 1H), 7.10 (bs, 2H), 3.95 (m, 1H), 3.66 (m,3H), 3.33 (m, 1H), 2.67 (m, 1H), 2.48 (m, 2H), 2.00 (m, 2H), 1.58 (m,1H), 1.04 (m, 10H).

EXAMPLE 543R,1S-7-[3-(1-N-ethylaminoethyl)-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid

A solution of 0.70 g (2.0 mmol) of1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid J, 0.31 g (2.2 mmol) of pyrrolidine 44, 0.61 g (6.0 mmol) oftriethylamine, and 20 mL of acetonitrile was heated at reflux for 4hours. The solution was cooled to room temperature and concentrated. Theresidue was taken up in water which was basified to pH 11.0, filteredthrough a fiberglass pad, neutralized to pH 7.9, and refrigerated. Thesolids that formed were filtered, washed with water and ether, and driedin vacuo to give 0.51 g of the title compound; mp 187°-189° C.

Anal. Calcd. for C₂₅ H₂₆ F₂₃ N₃ O₃.3.6H₂ O: C, 55.77; H, 6.20; N, 7.80.Found: C, 55.50; H, 6.23; N, 7.72.

¹ H-NMR (DMSO-d₆) δ8.67 (s, 1H), 7.88 (m, 1H), 7.72 (m, 1H), 7.43 (m,1H), 5.65 (d, J=7.7 Hz, 1H), 3.35 (m, 3H), 3.2 (m, 1H), 2.75 (d, J=3.3Hz, 3H), 2.63 (m, 1H), 2.43 (m, 2H), 2.1 (m, 1H), 1.90 (m, 1H), 1.57 (m,1H), 0.98 (m, 6H).

EXAMPLE 553R,1S-5-amino-7-[3-(1-N-ethylaminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

A solution of 0.56 g (2.0 mmol) of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid M, 0.31 g (2.2mmol) of pyrrolidine 44, 0.61 g (6.0 mmol) of triethylamine, and 20 mLof pyridine was heated at reflux for 24 hours. The solution was cooledto room temperature and concentrated. The residue was dissolved inwater, acidified to pH 2.0, filtered through a fiberglass pad, andlyophilized. The solids were suspended in concentrated hydrochloric acidand filtered, and the filtrate was concentrated. The residue wastriturated with 2-propanol:ether (1:1); the solids were filtered, washedwith chloroform and ether, and dried in vacuo to give 0.68 g of thetitle compound as the hydrochloride salt; mp >300° C.

Anal. Calcd. for C₂₁ H₂₇ FN₄ O₃.1.8HCl.1.5H₂ O: C, 50.94; H, 6.47; N,11.31; Cl, 12.91. Found: C, 50.71; H, 6.19; N, 11.25; Cl, 12.63.

¹ H-NMR (DMSO-d₆) δ8.42 (s, 1H), 6.38 (d, J=8 Hz, 1H), 3.83 (m, 1H),3.65 (m, 2H), 3.51 (m, 2H), 3.33 (m, 1H), 2.99 (m, 2H), 2.62 (m, 1H),2.13 (m, 1H), 1.81 (m, 1H), 1.30 (m, 8H), 1.04 (m, 2H).

EXAMPLE 563R,1S-5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[3-(1-N-methylaminoethyl)-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid

A solution of 0.71 g (2.3 mmol) of5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid K, 0.80 g (3.0 mmol) of pyrrolidine 60, 0.93 g (9.2 mmol) oftriethylamine, 15 mL of acetonitrile, and 15 mL of DMSO was refluxed for18 hours. The mixture was cooled to room temperature, and theacetonitrile was evaporated in vacuo. The solution was poured intowater, and the solids that formed were filtered, washed with water andether, and dried.

The above compound (1.07 g, 2.1 mmol) was dissolved in 30 mL ofchloroform, cooled to 5° C., and treated with a steady stream of gaseousHCl for 5 minutes. The mixture was stirred overnight at roomtemperature. The solution was then concentrated to a paste which wastaken up in a small amount of chloroform, diluted with ethyl acetate,cooled to 5° C., and filtered. The solids were washed with ethyl acetateand dried to give 0.95 g of the title compound as the hydrochloridesalt; mp 258°-260° C.

Anal. Calcd. for C₂₁ H₂₇ FN₄ O₄.2HCl.2H₂ O: C, 47.82; H, 6.31; N, 10.62;Cl, 13.44. Found: C, 47.81; H, 5.99; N, 10.78; Cl, 13.77.

¹ H-NMR (DMSO-d₆) δ8.52 (s, 1H), 4.02 (m, 1H), 3.74 (m, 2H), 3.58 (m,2H), 3.42 (s, 3H), 3.30 (m, 1H), 2.5 (m, 4H), 2.08 (m, 1H), 1.75 (m,1H), 1.30 (d, J=6.5 Hz, 3H), 1.14 (m, 1H), 0.96 (m, 2H), 0.76 (m, 1H).

EXAMPLE 573R,1S-1-cyclopropyl-8-ethoxy-6-fluoro-1,4-dihydro-7-[3-(1-N-methylaminoethyl)-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid

A solution of 0.35 g (1.0 mmol) of1-cyclopropyl-8-ethoxy-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid borondifluoride complex, 0.27 g (1.2 mmol) of pyrrolidine 60, 0.46g (3.6 mmol) of diisopropyiethylamine, and 15 mL of acetonitrile wasstirred at room temperature for 18 hours. The solution was concentratedto an oil which was chromatographed (silica gel 230-400 mesh, elutingwith 90:10 CHCl₃ :MeOH). The product that was isolated was dissolved in20 mL of ethanol, treated with 5 mL of triethylamine, and heated atreflux for 3 hours. The solution was cooled to 5° C. and diluted withether. The solids were filtered, washed with ether, and dried to give0.47 g of3R,1S-7-[3-(1-N-t-butoxycarbonyl-N-methylaminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-8-ethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid.

¹ H-NMR (CDCl₃) δ15.0 (br s, 1H), 3.77 (s, 1H), 7.76 (d, J=14 Hz, 1H),4.25 (m, 1H), 4.00 (m, 1H), 3.80 (m, 2H), 3.63 (m, 3H), 3.40 (m, 1H),2.75 (d, J=10 Hz, 3H), 2.35 (m, 1H), 2.10 (m, 1H), 1.7 (m, 1H), 1.46 (s,9H), 1.33 (m, 4H), 1.22 (d, J=6.7 Hz, 3H), 1.05 (m, 2H), 0.85 (m, 1H).

A solution of the above compound in 30 mL of chloroform was cooled to 5°C. and treated with a steady stream of gaseous HCl for 10 minutes. Themixture was warmed to room temperature and concentrated. The residue wastriturated with isopropanol:ether 1:10, and the solids were filtered andwashed with ether to give 0.37 g of the title compound as thehydrochloride salt; mp 210°-212° C.

Anal. Calcd. for C₂₂ H₂₈ FN₃ O₄.1.2HCl.1.15H₂ O: C, 54.83; H, 6.59; N,8.72; Cl, 8.83. Found: C, 54.93; H, 6.99; N, 9.09; Cl, 8.90.

¹ H-NMR (DMSO-d₆) δ15.1 (bs, 1H), 9.0 (bs, 1H), 8.67 (s, 1H), 7.66 (d,J=13.8 Hz, 1H), 4.14 (m, 1H), 3.74-3.4 (m, 4H), 3.07 (m, 3H), 2.56 (bs,3H), 2.12 (m, 1H), 1.75 (m, 1H), 1.28 (m, 4H), 1.20 (m, 4H), 1.17 (m,2H), 0.90 (m, 1H).

EXAMPLE 583R,1S-5-amino-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

A solution of 0.32 g (1.1 mmol) of5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid L, 0.26 g (1.2 mmol) of pyrrolidine 20, 0.32 g (3.2 mmol) oftriethylamine, and 15 mL of acetonitrile was heated at reflux for 6hours. The suspension was cooled to room temperature and filtered. Thesolids were washed with water and ether, dried, and then dissolved in 20mL of chloroform. The solution was cooled in an ice bath and treatedwith a steady stream of gaseous HCl for 10 minutes. The mixture wasallowed to warm to room temperature. The solvent was evaporated and theresidue was triturated with 30 mL of ethyl acetate. The solids werefiltered, washed with ether, and dried in vacuo to give 0.33 g of thetitle compound as the hydrochloride salt, mp 251°-254° C.

EXAMPLE 593R,1S-5-amino-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid

A solution of 0.34 g (1.1 mmol) of5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid K, 0.26 g (1.2 mmol) of pyrrolidine 20, 0.32 g (3.2 mmol) oftriethylamine, 10 mL of DMS 0, and 10 mL of acetonitrile was heated atreflux for 18 hours. The acetonitrile was evaporated in vacuo, and thesolution was poured into water and extracted with chloroform. Theorganic layer was dried and concentrated. The residue waschromatographed (silica gel, 230-400 mesh, eluting with 90:10 CHCl₃:MeOH) to give 0.37 g of5-amino-7-[(3R,1'S)-3-(1'-N-t-butoxycarbonylaminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid.

¹ H-NMR (CDCl₃) δ15.08 (s, 1H), 8.64 (s, 1H), 6.39 (bs, 2H), 4.44 (m,1H), 3.90-3.70 (m, 3H), 3.64 (m, 3H), 3.43 (s, 3H), 2.19 (m, 1H), 2.03(m, 1H), 1.69 (m, 1H), 1.45 (s, 9H), 1.23 (d, J=6.8 Hz, 3H), 1.20 (m,1H), 0.97 (m, 2H), 0.74 (m, 1H).

The above compound was dissolved in 20 mL of chloroform, cooled to 5°C., and treated with gaseous HCl for 10 minutes. The mixture was allowedto warm to room temperature and stirred at that temperature for 3 hours.The solution was concentrated to a paste which was triturated with ethylacetate and filtered. The solids were washed with ether and dried invacuo to give 0.27 g of the title compound as the hydrochloride salt; mp234°-237 ° C.

¹ H-NMR (DMSO-d₆) δ8.51 (s, 1H), 8.23 (bs, 2H), 4.04 (m, 1H), 3.70 (m,2H), 3.58 (m, 2H), 3.42 (s, 3H), 3.25 (m, 1H), 2.40 (m, 1H), 2.10 (m,1H), 1.70 (m, 1H), 1.30 (d, J=6.5 Hz, 3H), 1.15 (m, 1H), 0.96 (m, 2H),0.86 (m, 1H).

EXAMPLE 603R,1S-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8-trifluoromethyl-3-quinolinecarboxylicacid

A solution of 0.36 g (1.1 mmol) of1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-trifluoromethyl-3-quinolinecarboxylicacid D, 0.25 g (1.2 mmol) of pyrrolidine 20, 0.32 g (3.2 mmol) oftriethylamine, and 15 mL of acetonitrile was heated at reflux for 3hours, then cooled to room temperature and concentrated. The residue waschromatographed (silica gel, 230-400 mesh, eluting with 90:10 CHCl₃:MeOH) to give 0.53 g of3R,1S-7-[3-(1-N-t-butoxycarbonylaminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8-trifluoromethyl-3-quinolinecarboxylicacid.

¹ H-NMR (CDCl₃) δ8.78 (s, 1H), 7.94 (d, J=14.3 Hz, 1H), 4.40 (bd, 1H),3.98 (m, 2H), 3.76 (m, 4H), 2.30 (m, 1H), 2.10 (m, 1H), 1.75 (m, 1H),1.45 (bs, 9H), 1.24 (d, J=6.7 Hz, 3H), 1.21 (m, 2H), 1.05 (m, 1H), 0.8(m, 1H).

The above compound was dissolved in 20 mL of chloroform, cooled to 5°C., and treated with a steady stream of gaseous HCl for 10 minutes. Thesolution was allowed to warm to room temperature and concentrated byhalf. The suspension was diluted with ether and filtered; the solidswere washed with ether and dried in vacuo to give 0.42 g of the titlecompound as the hydrochloride salt, mp >300° C.

Anal. Calcd. for C₂₀ H₂₁ F₄ N₃ O₃.1.8HCl.1.3H₂ O: C, 46.51; H, 4.95; N,8.14; Cl, 12.36. Found: C, 46.48; H, 4.79; N, 8.15; Cl, 12.40.

¹ H-NMR (DMSO-d₆) δ8.76 (s, 1H), 8.32 (bs, 3H), 7.86 (d, J=14.6 Hz, 1H),3.93 (m, 3H), 3.73 (m, 2H), 3.27 (m, 1H), 2.50 (m, 1H), 2.11 (m, 1H),1.75 (m, 1.27 (d, 3H), 1.20 (m, 2H), 1.02 (m, 1H), 0.87 1H).

EXAMPLE 613R,1S-1-cyclopropyl-6-fluoro-7-[3-(1-N-methylaminoethyl)-1-pyrrolidinyl]-5-methyl-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

From 1.0 g (2.8 mmol) of 7-fluoro-5-methyl-8-methoxyquinoline borateester (from quinolone N), and 0.84 g (3.2 mmol) of pyrrolidine 60, anddiisopropyiethylamine (11.2 mmol) in acetonitrile was obtained 1.38 g(87%) of the desired product.

¹ H-NMR (DMSO-d₆) δ0.9-1.28 (m, 10H), 1.38 (s, 9H), 1.60-1.68 (m, 1H),2.1-2.8 (m, 1H), 2.40-2.58 (m, 1H), 2.60-2.70 (d, 6H), 3.48 (s, 3H),3.5-4.2 (m, 3H), 4.23-4.38 (m, 1H), 8.9 (s, 1H). M+1 566.

From 1.3 g (2.3 mmol) of the borate ester obtained above, 2.6 mmol oftriethylamine and 60 mL of 80% ethanol was obtained 0.92 g (78%) of theester which was purified by chromatography (silica gel, 10% CH₃OH/CHCl₃).

¹ H-NMR (DMSO-d₆) δ0.65-0.99 (m, 3H), 1.05-1.30 (m, 4H), 1.37 (s, 9H),1.46-1.55 (m, 1H), 1.98-2.10 (m, 1H), 2.37-2.50 (m, 1H), 2.66 (d, 6H),3.45 (s, 3H), 3.38-3.62 (m, 2H), 3.70-3.90 (m, 1H), 3.9-4.2 (m, 2H),8.62 (s, 1H), 15.61 (s, 1H).

Anal. Calcd. for C₂₇ H₃₆ F₁ N₃ O₆.0.5H₂ O: C, 61.56; H, 7.08; N, 7.98.Found: C, 61.51; H, 6.80; N, 8.12.

From 0.90 g (1.74 mmol) of the ester above, using Method C andrecrystallizing from ethanol, the title compound was obtained (0.51 g,70%); mp 238°-241° C. (dec).

¹ H-NMR (TFA) δ1.02-1.38 (dm, 2H), 1.39-1.76 (m, 2H), 1.68 (d, J-6.57Hz, 3H), 2.22-2.42 (m, 1H), 2.48-2.70 (m, 1H), 2.94 (s, 3H), 3.05 (s,3H), 3.18-3.38 (m, 1H), 3.62-3.82 (m, 1H), 3.94 (s, 3H), 4.10-4.61 (m,5H), 9.46 (s, 1H), 11.6 (s, 1H).

Anal. Calcd. for C₂₂ H₂₈ N₃ F₁ O₄.HCl: C, 58.21; H, 6.44; N, 9.26.Found: C, 58.08; H, 6.41; N, 9.39.

EXAMPLE 623R,1S-1-difluorophenyl-6-fluoro-7-[3-(1-N-methylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

From 0.46 g (1.07 mmol) of1-(2,4-difluorophenyl)-6,7-difluoro-5-methyl-8-methoxyquinoline borateester (from quinolone N), 0.29 g (1.12 mmol) of pyrrolidine 60, and 4.28mmol of diisopropyiethylamine was obtained the coupled product. Theresulting borate ester was carried on as described above to provide 0.17g (61%) of the N-t-butoxycarbonyl derivative after chromatography (10%CH₃ OH/CHCl₃).

¹ H-NMR (CDCl₃) δ1.12-1.70 (m, 3H), 1.42 (d, 3H), 1.59 (s, 9H), 2.69,2.73 (2d, 3H), 2.81 (d, J=3.19 Hz, 3H), 3.02, 3.14 (2s, 3H), 3.20-4.30(m, 7H), 6.8-7.5 (m, 3H), 8.40-8.45 (m, 1H).

From 0.16 g (0.27 mmol) of the above compound, the protecting group wasremoved using Method C. After recrystallizing from isopropanol, thetitle compound was obtained, 0.09 g (70%) as an off-white solid; mp233°-238° C. (dec).

Anal. Calcd. for C₂₅ H₂₆ F₃ N₃ O₄.HCl.0.5H₂ O: C, 56.13; H, 5.28; N,7.85. Found: C, 56.21; H, 0.18; N, 7.89.

¹ H-NMR (TFA) δ1.62 (d, J=5.5 Hz, 3H), 2.09 (m, 1H), 2.4 (m, 1H), 2.98(m, 1H), 2.97 (s, 3H), 3.01 (s, 3H), 3.28, 3.39 (2s, 3H), 3.65 (m, 1H),4.09 (m, 5H), 7.18 (m, 2H), 7.72 (m, 1H), 8.99 (s, 1H), 11.63 (s, 1H).

EXAMPLE 633R,1R-1-(2,4-difluorophenyl)-5-methyl-7-[3-(1-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

From 0.70 g (2.0 mmol) of1-(2,4-difluorophenyl)-5-methyl-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, J, 0.57 g (2.5 mmol) of pyrrolidine 61, and 1.03 g (8.0 mmol) ofdiisopropyiethylamine, there was obtained the title compound (0.93 g).

¹ H-NMR (CDCl₃) δ1.07-1.15 (m, 3H), 1.45 (s, 9H), 1.65-1.79 (m, 1H),1.82-2.01 (m, 1H), 2.25-2.40 (m, 1H), 2.68-2.73 (m, 3H), 2.80 (d, 3H),3.11-3.40 (m, 3H), 3.50-3.63 (m, 1H), 3.80-4.20 (2×m, 1H), 5.60 (br d,1H), 7.07-7.21 (m, 2H), 7.40-7.52 (m, 1H), 8.47 (s, 1H), 15.60-15.72 (m,1H).

Anal. Calcd. for C₂₉ H₃₂ F₃ N₃ O₅ : C, 62.25; H, 5.76; N, 7.51. Found:C, 61.90; H, 5.66; N, 7.51.

3R,1R-1-(2,4-difluorophenyl)-5-methyl-7-[3-(1-N-methylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

From 0.80 g (1.4 mmol) of3R,1R-1-(2,4-difluorophenyl)-5-methyl-7-[3-(1-N-tert-butoxycarbonyl-N-methylaminoethyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, hydrolysis of the tert-butoxycarbonyl group with trifluoroaceticacid in dichloromethane provided the title compound (0.72 g); mp140°-143° C.

¹ H-NMR (DMSO-d₆) δ1.16 (d, 3H, J=6.1 Hz), 1.63-1.78 (m, 1H), 2.02-2.18(m, 1H), 2.32-2.60 (m, 1H), 2.50 (s, 3H), 2.78 (d, 3H, J=3.1 Hz),3.14-3.40 (m, 4H), 3.50-3.65 (m, 1H), 5.71 (d, 1H, J=7.9 Hz), 7.37-7.49(m, 1H), 7.65-7.79 (m, 1H), 7.82-7.95 (m, 1H), 8.20-8.70 (m, 2H), 8.69(s, 1H).

Anal. Calcd. for C₂₄ H₂₄ F₃ N₃ O₃.1.0CF₃ CO)₂ H.0.6H₂ O: C, 53.45; H,4.52; N, 7.19. Found: C, 53.47; H, 4.32; N, 7.45.

EXAMPLE 643R,1S-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-1,8-naphthyridine-3-carboxylicacid, monohydrochloride

A mixture of7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid G (0.50 g, 1.41 mmol), compound 60 (0.38 g, 1.66 mmol), Et₃ N (1mL, 7.18 mmol) in CH₃ CN (20 mL) was heated at reflux for 3 hours. Themixture was cooled and concentrated. The residue was dissolved in CH₂Cl₂ (50 mL), cooled to 0° C. and HCl was bubbled into the solution for 2minutes. The reaction was allowed to warm to room temperature for 18hours and concentrated. The residue was recrystallized from EtOH/H₂ O toprovide 0.56 g (82%) of the desired product; mp 278°-280° C. (dec).

NMR (DMSO-d₆) δ1.21 (d, 3H), 1.66 (m, 1H), 2.01 (m, 1H), 3.22 (m, 2H),3.34 (s, 3H), 7.34 (t, 1H), 7.59 (t, 1H), 7.82 (q, 1H), 8.06 (d, 1H),8.81 (s, 1H), 8.98 (bs, 2H).

EXAMPLE 653R,1S-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid, monohydrochloride

A mixture of6,7-difluoro-1-(2,4-difluorophenyl)-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid J (0.41 g, 1.20 mmol), compound 20 (0.36 g, 1.44 mmol), ET₃ N (1mL, 7.18 mmol) in CH₃ CN (25 mL) was heated at reflux for 3 hours. Thereaction was worked up as described previously to provide 0.51 g (87%)of the desired product; mp >250° C.

NMR (DMSO-d₆) δ1.22 (d, 3H), 1.75 (, 1H), 2.03 (m, 1H), 2.37 (m, 1H),2.77 (m, 3H), 3.78 (m, 1H), 5.75 (d, 1H), 7.43 (t, 1H), 7.73 (t, 1H),7.90 (t, 1H), 8.19 (bs, 2H), 8.66 (s, 1H).

EXAMPLE 663R,1S-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-5-methyl-7-[3-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid, monohydrochloride

A mixture of6,7-difluoro-1-(2,4-difluorophenyl)-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid J (0.50 g, 1.47 mmol), compound 60 (0.38 g, 1.66 mmol), Et₃ N (1mL, 7.18 mmol) in CH₃ CN 920 mL) was heated at reflux for 5 hours. Themixture was then cooled and concentrated. The residue was dissolved inCH₂ Cl₂ (50 mL), cooled to 0° C. and HCl was bubbled into the solutionfor 2 minutes. The reaction was then allowed to stir at room temperaturefor 18 hours, and then concentrated. The residue was recrystallized fromEtOH/H₂ O to provide 0.58 g (78%) of the desired product; mp >300° C.(dec.).

NMR (DMSO-d₆) δ1.24 (d, 3H), 1.69 (m, 1H), 2.01 (m, 1H), 2.77 (d, 3H),3.33 (m, 6H), 3.67 (m, 1H), 5.73 (d, 1H), 7.42 (t, 1H), 7.70 (t, 1H),7.89 (q, 1H), 8.66 (s, 1H).

EXAMPLE 673R,1S-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid, monohydrochloride

A mixture of1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid I (0.41 g, 1.47 mmol), compound 60 (0.41 g, 1.55 mmol), Et₃ N (1mL, 7.13 mmol) and CH₃ CN (20 mL) was heated at reflux for 3 hours.Workup was performed as described above to provide 0.49 g (79%) of thedesired product; mp >250° C.

NMR (DMSO-d₆ -TFA) δ1.11 (m, 2H), 1.31 (d, 3H), 1.38 (m, 2H), 1.79 (m,1H), 2.52 (s, 2H), 2.71 (d, 3H), 3.34 (t, 1H), 3.48 (t, 1H), 3.67. (m,3H), 3.86 (m, 1H), 7.01 (d, 1H), 8.53 (s, 1H).

EXAMPLE 683R,1S-5-amino-1-cyclopropyl-6-fluoro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid, monohydrochloride

A mixture of5-amino-1-cyclopropyl-6,7-difluoro-4-oxo-3-quinolinecarboxylic acid M(0.40 g, 1.42 mmol), compound 60 (0.42 g, 1.68 mmol), Et₃ N (1 mL, 7.18mmol) in pyridine (20 mL) was heated at reflux for 7 hours and thenstirred at room temperature for 12 hours. The mixture was concentratedand chromatographed (silica gel, 5% MeOH/CHCl₃) to provide 0.60 g ofmaterial.

NMR (CDCl₃) δ1.07 (m, 2H), 1.23 (m, 5H), 1.45 (m, 9H), 2.15 (m, 1H),2.56 (m, 1H), 2.78 (m, 3H), 3.28-3.85 (m, 6H), 6.14 (d, 1H), 6.46 (bs,2H), 8.52 (s, 1H).

This material was dissolved in CHCl₂ (25 mL), cooled to 0° C. and HClwas bubbled in for 2 minutes. The mixture was allowed to warm to roomtemperature, stirred for 18 hours, and concentrated. The residue wasrecrystallized from EtOH/H₂ O to provide 0.28 g (45%) of the desiredproduct; mp >250° C.

NMR (DMSO-d₆) δ1.05 (6s, 2H), 1.30 (m, 6H), 1.73 (m, 1H), 2.15 (m, 1H),2.56 (s, 3H), 3.28-3.85 (m, 6H), 6.37 (d, 1H), 7.18 (bs, 1H), 8.41 (s,1H), 9.11 (bs, 2H).

EXAMPLE 693S,1R-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid

The title compound was prepared from naphthyridine A, pyrrolidine 35,and triethylamine using the procedure outlined in Example 50; mp231°-234° C.

EXAMPLE 703S,1S-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid

The title compound was prepared from naphthyridine A, pyrrolidine 34,and triethylamine using the procedure outlined in Example 50; mp226°-228° C.

EXAMPLE 713R,1S-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid

The title compound was prepared from naphthyridine A, pyrrolidine 32,and triethylamine using the procedure outlined in Example 50; mp231°-233° C.

EXAMPLE 723R,1R-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4,-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid

The title compound was prepared from naphthyridine A, pyrrolidine 33,and triethylamine using the procedure outlined in Example 50; mp228°-230° C.

EXAMPLE 733R,1S-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

The title compound was prepared from quinolone B, pyrrolidine 32, andtriethylamine as outlined in Example 14; mp 273°-275° C.

EXAMPLE 743R,1R-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

The title compound was prepared from quinolone B, pyrrolidine 33, andtriethylamine as outlined in Example 14; mp 263°-265° C.

EXAMPLE 753S,1R-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

The title compound was prepared from quinolone B, pyrrolidine 35, andtriethylamine as outlined in Example 14; mp 262°-264° C.

EXAMPLE 763S,1S-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid

The title compound was prepared from quinolone B, pyrrolidine 34, andtriethylamine as outlined in Example 14; mp 271°-274° C.

EXAMPLE 773R,1R-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid

The title compound was prepared from naphthyridine A, pyrrolidine 45,and triethylamine using the procedure outlined in Example 50.

Anal. Calcd. for C₂₀ H₂₅ FN₄ O₃.0.05 HF: C, 59.75; H, 6.63; N, 13.94; F,4.96. Found: C, 59.72; H, 6.75; N, 14.23; F, 5.18.

EXAMPLE 783R,1S-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid

The title compound was prepared from naphthyridine A, pyrrolidine 44,and triethylamine using the procedure outlined in Example 50.

Anal. Calcd. for C₂₀ H₂₅ FN₄ O₃.0.1 HF.0.4 H₂ O: C, 60.41; H, 6.57; N,14.09; F, 5.26. Found: C, 60.75; H, 6.52; N, 13.61; F, 5.19.

EXAMPLE 793S,1R-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid

The title compound was prepared from naphthyridine A, pyrrolidine 47,and triethylamine using the procedure outlined in Example 50.

Anal. Calcd. for C₂₀ H₂₅ FN₄ O₃.0.45 H₂ O: C, 60.58; H, 6.58; N, 14.13;F, 4.79. Found: C, 60.57; H, 6.47; N, 14.29; F, 5.01.

EXAMPLE 803S,1S-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid

The title compound was prepared from naphthyridine A, pyrrolidine 46,and triethylamine using the procedure outlined in Example 50.

Anal. Calcd. for C₂₀ H₂₅ FN₄ O₃.0.5 H₂ O: C, 60.44; H, 6.59; N, 14.10;F, 4.78. Found: C, 60.83; H, 6.40; N, 14.15; F, 4.86.

We claim:
 1. An individual stereoisomer of a compound of the formula##STR18## wherein * denotes an asymmetric carbon atom;X is C--OR; R₁ isethyl, cyclopropyl, or 2,4-difluorophenyl; R₂ is hydrogen, alkyl of 1-4carbon atoms or a cation; R₃ is hydrogen, amino, or methyl; R and R' areeach independently hydrogen or alkyl of 1-carbon atoms, or apharmaceutically acceptable acid addition salt thereof.
 2. Theindividual stereoisomers of claim 1 wherein R₁ is cyclopropyl.
 3. Thestereoisomers of claim 1 wherein R₁ is 2,4-difluorophenyl.
 4. Thestereoisomers of claim 1 wherein R₃ is amino.
 5. The stereoisomers ofclaim 1 wherein R₃ is methyl.
 6. The stereoisomer of claim 1 and being3R,1S-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid.
 7. The stereoisomer of claim 1 and being3R,1S-5-amino-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid.
 8. The stereoisomer of claim 1 and being3R,1S-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid.
 9. The stereoisomer of claim 1 and being3R,1S-5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid.
 10. The stereoisomer of claim 1 and being3R,1S-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid.
 11. The stereoisomer of claim 1 and being3R,1S-5-amino-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid.
 12. The stereoisomer of claim 1 and being3R,1S-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid.
 13. The stereoisomer of claim 1 and being3R,1S-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid.
 14. The stereoisomer of claim 1 and being3S,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid.
 15. The stereoisomer of claim 1 and being3S,1R-5-amino-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid.
 16. The stereoisomer of claim 1 and being3S,1R-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid.
 17. The stereoisomer of claim 1 and being3S,1R-5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid.
 18. The stereoisomer of claim 1 and being3S,1R-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid.
 19. The stereoisomer of claim 1 and being3S,1R-5-amino-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid.
 20. The stereoisomer of claim 1 and being3S,1R-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid.
 21. The stereoisomer of claim 1 and being3S,1R-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid.
 22. The stereoisomer of claim 1 and being3R,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid.
 23. The stereoisomer of claim 1 and being3R,1R-5-amino-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid.
 24. The stereoisomer of claim 1 and being3R,1R-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid.
 25. The stereoisomer of claim 1 and being3R,1R-5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid.
 26. The stereoisomer of claim 1 and being3R,1R-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid.
 27. The stereoisomer of claim 1 and being3R,1R-5-amino-1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid.
 28. The stereoisomer of claim 1 and being3R,1R-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid.
 29. The stereoisomer of claim 1 and being3R,1R-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid.
 30. The stereoisomer of claim 1 and being3R,1S-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-8-ethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid.
 31. The stereoisomer of claim 1 and being3R,1S-1-cyclopropyl-8-ethoxy-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid.
 32. The stereoisomer of claim 1 and being3R,1S-1-cyclopropyl-8-ethoxy-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid.
 33. The stereoisomer of claim 1 and being3R,1S-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-8-ethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid.
 34. The stereoisomer of claim 1 and being3S,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-8-ethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid.
 35. The stereoisomer of claim 1 and being3S,1R-1-cyclopropyl-8-ethoxy-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid.
 36. The stereoisomer of claim 1 and being3S,1R-1-cyclopropyl-8-ethoxy-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid.
 37. The stereoisomer of claim 1 and being3S,1R-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-8-ethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid.
 38. The stereoisomer of claim 1 and being3R,1R-7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-8-ethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid.
 39. The stereoisomer of claim 1 and being3R,1R-1-cyclopropyl-8-ethoxy-6-fluoro-1,4-dihydro-7-[3-[1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-3-quinolinecarboxylicacid.
 40. The stereoisomer of claim 1 and being3R,1R-1-cyclopropyl-8-ethoxy-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid.
 41. The stereoisomer of claim 1 and being3R,1R-1-cyclopropyl-7-[3-[1-(dimethylamino)ethyl]-1-pyrrolidinyl]-8-ethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid.
 42. A pharmaceutical composition comprising an antibacteriallyeffective amount of a compound of claim 1 in admixture with apharmaceutically acceptable carrier.
 43. A method of treating bacterialinfections in mammals which comprises administering to said mammal inneed thereof a pharmaceutical composition of claim
 42. 44. A process forthe preparation of a compound of claim 1 which comprises reacting acompound of the formula ##STR19## wherein L is fluorine or chlorine withan individual stereoisomeric amine of the formula ##STR20## wherein *denotes an asymmetric carbon atom;R is hydrogen or alkyl of 1-carbonatoms; and R" is hydrogen, alkyl of 1-carbon atoms or an aminoprotecting group, and removing, if necessary, the amino protecting groupaccording to known methods.